3hiz - Revision history

OCA at 07:22, 6 September 2023

OCA — Wed, 06 Sep 2023 07:22:09 GMT

←Older revision		Revision as of 07:22, 6 September 2023
Line 3:		Line 3:
	<StructureSection load='3hiz' size='340' side='right'caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>		<StructureSection load='3hiz' size='340' side='right'caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>
-	</td></tr><tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat"~~><div style='overflow: auto; max-height: 3em;'>[[3hhm\|3hhm]]</div></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 3.3Å</td></tr>
-	~~<tr~~ id~~='gene'><td class~~="~~sblockLbl~~">~~<b>~~[[~~Gene~~\|~~Gene:~~]]~~</b></td><td class="sblockDat">PIK3CA ([https://www~~.~~ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info~~&~~srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>	+
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [https://pdbe.org/3hiz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [https://www.ebi.ac.uk/pdbsum/3hiz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hiz ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [https://pdbe.org/3hiz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [https://www.ebi.ac.uk/pdbsum/3hiz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hiz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[https://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[https://omim.org/entry/612918 612918]]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>	+	[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[https://omim.org/entry/182000 182000]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[https://omim.org/entry/612918 612918]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[https://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref>	+	[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 39:		Line 37:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]~~	+	[[Category: Amzel LM]]
-	[[Category: Amzel~~, L M~~]]	+	[[Category: Gabelli SB]]
-	[[Category: Gabelli~~, S B~~]]	+	[[Category: Mandelker D]]
-	[[Category: Mandelker, D]]	+	[[Category: Vogelstein B]]
-	[[Category: Vogelstein, B]]	+
-	~~[[Category: 5-triphosphate]]~~	+
-	~~[[Category: Alternative splicing]]~~	+
-	~~[[Category: Atp-binding]]~~	+
-	~~[[Category: Disease mutation]]~~	+
-	~~[[Category: H1047r]]~~	+
-	~~[[Category: Host-virus interaction]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Nucleotide-binding]]~~	+
-	~~[[Category: Oncogene]]~~	+
-	~~[[Category: P110]]~~	+
-	~~[[Category: P85]]~~	+
-	~~[[Category: Phosphatidilynositol 3]]~~	+
-	~~[[Category: Phosphoprotein]]~~	+
-	~~[[Category: Pi3k]]~~	+
-	~~[[Category: Pi3kca]]~~	+
-	~~[[Category: Pik3r1]]~~	+
-	~~[[Category: Polymorphism]]~~	+
-	~~[[Category: Sh2 domain]]~~	+
-	~~[[Category: Sh3 domain]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-oncoprotein complex]]~~	+
-	~~[[Category: Ubl conjugation~~]]	+

OCA at 12:00, 13 October 2021

OCA — Wed, 13 Oct 2021 12:00:19 GMT

←Older revision		Revision as of 12:00, 13 October 2021
Line 1:		Line 1:

	==Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha==		==Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha==
-	<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>	+	<StructureSection load='3hiz' size='340' side='right'caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>
-	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3hhm\|3hhm]]</td></tr>	+	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3hhm\|3hhm]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [~~http~~://pdbe.org/3hiz PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3hiz PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3hiz ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [https://pdbe.org/3hiz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [https://www.ebi.ac.uk/pdbsum/3hiz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hiz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[~~http~~://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[~~http~~://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[~~http~~://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[~~http~~://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[~~http~~://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[~~http~~://omim.org/entry/612918 612918]]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>	+	[[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[https://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[https://omim.org/entry/612918 612918]]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[~~http~~://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref>	+	[[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[https://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hi/3hiz_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hi/3hiz_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 32:		Line 32:
	</div>		</div>
	<div class="pdbe-citations 3hiz" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3hiz" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphoinositide 3-kinase 3D structures\|Phosphoinositide 3-kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 37:		Line 40:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
	[[Category: Amzel, L M]]		[[Category: Amzel, L M]]

OCA at 07:38, 1 November 2017

OCA — Wed, 01 Nov 2017 07:38:34 GMT

←Older revision		Revision as of 07:38, 1 November 2017
Line 1:		Line 1:
		+
	==Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha==		==Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha==
	<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>		<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>
Line 6:		Line 7:
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [http://pdbe.org/3hiz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [http://www.ebi.ac.uk/pdbsum/3hiz PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [http://pdbe.org/3hiz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [http://www.ebi.ac.uk/pdbsum/3hiz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3hiz ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 31:		Line 32:
	</div>		</div>
	<div class="pdbe-citations 3hiz" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3hiz" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
	== References ==		== References ==
	<references/>		<references/>
Line 45:		Line 43:
	[[Category: Vogelstein, B]]		[[Category: Vogelstein, B]]
	[[Category: 5-triphosphate]]		[[Category: 5-triphosphate]]
		+	[[Category: Alternative splicing]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]
	[[Category: Disease mutation]]		[[Category: Disease mutation]]
Line 59:		Line 58:
	[[Category: Pi3kca]]		[[Category: Pi3kca]]
	[[Category: Pik3r1]]		[[Category: Pik3r1]]
		+	[[Category: Polymorphism]]
	[[Category: Sh2 domain]]		[[Category: Sh2 domain]]
	[[Category: Sh3 domain]]		[[Category: Sh3 domain]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Transferase-oncoprotein complex]]		[[Category: Transferase-oncoprotein complex]]
		+	[[Category: Ubl conjugation]]

OCA at 09:22, 8 February 2016

OCA — Mon, 08 Feb 2016 09:22:29 GMT

←Older revision		Revision as of 09:22, 8 February 2016
Line 2:		Line 2:
	<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>		<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3hhm\|3hhm]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3hhm\|3hhm]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~]), GRB1, PI3KR1, PIK3R1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRB1, PI3KR1, PIK3R1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [http://www.ebi.ac.uk/pdbsum/3hiz PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [http://pdbe.org/3hiz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [http://www.ebi.ac.uk/pdbsum/3hiz PDBsum]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 20:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3hiz ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 30:		Line 30:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 3hiz" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 37:		Line 38:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
	[[Category: Amzel, L M]]		[[Category: Amzel, L M]]

OCA at 08:00, 20 January 2015

OCA — Tue, 20 Jan 2015 08:00:59 GMT

←Older revision		Revision as of 08:00, 20 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_3hiz~~\| ~~PDB~~=3hiz \| ~~SCENE~~= }}	+	==Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha==
-	===~~Crystal~~ structure of p110alpha ~~H1047R~~ mutant in complex with ~~niSH2~~ of p85alpha~~===~~	+	<StructureSection load='3hiz' size='340' side='right' caption='[[3hiz]], [[Resolution\|resolution]] 3.30Å' scene=''>
-	~~{{ABSTRACT_PUBMED_19805105}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3hiz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HIZ FirstGlance]. <br>
		+	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3hhm\|3hhm]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), GRB1, PI3KR1, PIK3R1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hiz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3hiz RCSB], [http://www.ebi.ac.uk/pdbsum/3hiz PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[http://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[http://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[http://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[http://omim.org/entry/612918 612918]]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[http://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hi/3hiz_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110alpha, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110alpha in complex with two interacting domains of its regulatory partner (p85alpha), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85alpha is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110alpha. Moreover, we found that Arg-1047 points toward the cell membrane, perpendicular to the orientation of His-1047 in the WT enzyme. Surprisingly, two loops of the kinase domain that contact the cell membrane shift conformation in the oncogenic mutant. Biochemical assays revealed that the enzymatic activity of the p110alpha His1047Arg mutant is differentially regulated by lipid membrane composition. These structural and biochemical data suggest a previously undescribed mechanism for mutational activation of a kinase that involves perturbation of its interaction with the cellular membrane.

-	~~==Disease==~~	+	A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.,Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105<ref>PMID:19805105</ref>
-	[[http://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the ~~most common type. Breast cancer is etiologically~~ and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the ~~same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[http://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue~~. ~~Although many histologic types of ovarian neoplasms have been described~~, ~~epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms~~, ~~even of late~~-~~stage disease~~, ~~are vague. Consequently~~, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[http://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[http://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, ~~light brown~~, ~~flat macules. The lesions may be sparse or numerous. As they initially grow~~, ~~they develop a velvety to finely verrucous surface~~, ~~followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance~~.~~<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi~~ (~~CLOVE~~) ~~[MIM~~:~~[http://omim~~.~~org/entry/612918 612918]]~~. ~~CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings~~: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:~~22658544~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http://www.uniprot.org/uniprot~~/~~PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol)~~, ~~PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays~~ a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the ~~PDPK1-AKT1 pathway~~. ~~Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway~~. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[http://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<~~ref~~>~~PMID:7518429~~</~~ref~~>~~<ref>PMID:17626883</ref><ref>PMID:19805105</ref>~~	+	</div>
-		+
-	~~==About this Structure==~~	+
-	[[3hiz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA].	+

	==See Also==		==See Also==
	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]		*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
-	*[[Phsphatidylinositol 3-kinase\|Phsphatidylinositol 3-kinase]]	+	== References ==
-		+	<references/>
-	==~~Reference~~==	+	__TOC__
-	~~<ref group="xtra">PMID:019805105</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
-	[[Category: Amzel, L M.]]	+	[[Category: Amzel, L M]]
-	[[Category: Gabelli, S B.]]	+	[[Category: Gabelli, S B]]
-	[[Category: Mandelker, D.]]	+	[[Category: Mandelker, D]]
-	[[Category: Vogelstein, B.]]	+	[[Category: Vogelstein, B]]
	[[Category: 5-triphosphate]]		[[Category: 5-triphosphate]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]

OCA at 09:26, 24 March 2013

OCA — Sun, 24 Mar 2013 09:26:21 GMT

←Older revision		Revision as of 09:26, 24 March 2013
Line 2:		Line 2:
	===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===		===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===
	{{ABSTRACT_PUBMED_19805105}}		{{ABSTRACT_PUBMED_19805105}}
		+
		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[http://omim.org/entry/167000 167000]]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[http://omim.org/entry/114550 114550]].<ref>PMID:15608678</ref> Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[http://omim.org/entry/182000 182000]]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref> Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[http://omim.org/entry/612918 612918]]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> [[http://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref><ref>PMID:17626883</ref><ref>PMID:19805105</ref>

	==About this Structure==		==About this Structure==
Line 11:		Line 17:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:019805105</ref><references group="xtra"/>	+	<ref group="xtra">PMID:019805105</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]

OCA at 09:17, 11 March 2013

OCA — Mon, 11 Mar 2013 09:17:36 GMT

←Older revision		Revision as of 09:17, 11 March 2013
Line 1:		Line 1:
-	[[Image:3hiz.png\|left\|200px]]
-
	{{STRUCTURE_3hiz\| PDB=3hiz \| SCENE= }}		{{STRUCTURE_3hiz\| PDB=3hiz \| SCENE= }}
-
	===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===		===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===
-
	{{ABSTRACT_PUBMED_19805105}}		{{ABSTRACT_PUBMED_19805105}}

OCA at 09:41, 20 October 2012

OCA — Sat, 20 Oct 2012 09:41:30 GMT

←Older revision		Revision as of 09:41, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3hiz]] is a 2 chain structure ~~of [[Phosphoinositide 3-Kinases]]~~ with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA].	+	[[3hiz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIZ OCA].

	==See Also==		==See Also==

OCA at 23:39, 25 July 2012

OCA — Wed, 25 Jul 2012 23:39:59 GMT

←Older revision		Revision as of 23:39, 25 July 2012
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	[[Image:3hiz.png\|left\|200px]]		[[Image:3hiz.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3hiz", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3hiz\| PDB=3hiz \| SCENE= }}		{{STRUCTURE_3hiz\| PDB=3hiz \| SCENE= }}

	===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===		===Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_19805105}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 19805105 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_19805105}}		{{ABSTRACT_PUBMED_19805105}}

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	==See Also==		==See Also==
-	*[[Phosphoinositide 3-Kinases]]	+	*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
		+	*[[Phsphatidylinositol 3-kinase\|Phsphatidylinositol 3-kinase]]

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~19805105~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:019805105</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]		[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
Line 33:		Line 23:
	[[Category: Vogelstein, B.]]		[[Category: Vogelstein, B.]]
	[[Category: 5-triphosphate]]		[[Category: 5-triphosphate]]
-	[[Category: Alternative splicing]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]
	[[Category: Disease mutation]]		[[Category: Disease mutation]]
Line 48:		Line 37:
	[[Category: Pi3kca]]		[[Category: Pi3kca]]
	[[Category: Pik3r1]]		[[Category: Pik3r1]]
-	[[Category: Polymorphism]]
	[[Category: Sh2 domain]]		[[Category: Sh2 domain]]
	[[Category: Sh3 domain]]		[[Category: Sh3 domain]]
	[[Category: Transferase]]		[[Category: Transferase]]
-	[[Category: Transferase/oncoprotein complex]]	+	[[Category: Transferase-oncoprotein complex]]
-	~~[[Category: Ubl conjugation~~]]	+

OCA: Protected "3hiz" [edit=sysop:move=sysop]

OCA — Sun, 26 Dec 2010 08:40:08 GMT

Protected "3hiz" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:40, 26 December 2010