4c7t

From Proteopedia

(Difference between revisions)

Revision as of 22:44, 25 December 2014

Focal Adhesion Kinase catalytic domain in complex with a diarylamino- 1,3,5-triazine inhibitor

Structural highlights

4c7t is a 1 chain structure with sequence from Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[FAK1_CHICK] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development, embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), ephrin receptors, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Regulates P53/TP53 activity and stability. Phosphorylates SRC; this increases SRC kinase activity. Isoform 2 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

FAK and FGFR2 signaling pathways play important roles in cancer development, progression and tumor angiogenesis. PHM16 is a novel ATP competitive inhibitor of FAK and FGFR2. To evaluate the therapeutic efficacy of this agent, we examined its anti-angiogenic effect in HUVEC and its anti-tumor effect in different cancer cell lines. We showed PHM16 inhibited endothelial cell viability, adherence and tube formation along with the added ability to induce endothelial cell apoptosis. This compound significantly delayed tumor cell growth. Together, these data showed that inhibition of both FAK and FGFR2 signaling pathways can enhance anti-tumor and anti-angiogenic activities.

Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities.,Dao P, Jarray R, Smith N, Lepelletier Y, Coq JL, Lietha D, Hadj-Slimane R, Herbeuval JP, Garbay C, Raynaud F, Chen H Cancer Lett. 2014 Mar 19. pii: S0304-3835(14)00152-9. doi:, 10.1016/j.canlet.2014.03.007. PMID:24657306^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ren XR, Ming GL, Xie Y, Hong Y, Sun DM, Zhao ZQ, Feng Z, Wang Q, Shim S, Chen ZF, Song HJ, Mei L, Xiong WC. Focal adhesion kinase in netrin-1 signaling. Nat Neurosci. 2004 Nov;7(11):1204-12. Epub 2004 Oct 17. PMID:15494733 doi:10.1038/nn1330
↑ Li W, Lee J, Vikis HG, Lee SH, Liu G, Aurandt J, Shen TL, Fearon ER, Guan JL, Han M, Rao Y, Hong K, Guan KL. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nat Neurosci. 2004 Nov;7(11):1213-21. Epub 2004 Oct 17. PMID:15494734 doi:10.1038/nn1329
↑ Liu G, Beggs H, Jurgensen C, Park HT, Tang H, Gorski J, Jones KR, Reichardt LF, Wu J, Rao Y. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nat Neurosci. 2004 Nov;7(11):1222-32. Epub 2004 Oct 17. PMID:15494732 doi:10.1038/nn1331
↑ Koshman YE, Kim T, Chu M, Engman SJ, Iyengar R, Robia SL, Samarel AM. FRNK inhibition of focal adhesion kinase-dependent signaling and migration in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2226-33. doi:, 10.1161/ATVBAHA.110.212761. Epub 2010 Aug 12. PMID:20705914 doi:10.1161/ATVBAHA.110.212761
↑ Koshman YE, Chu M, Engman SJ, Kim T, Iyengar R, Robia SL, Samarel AM. Focal adhesion kinase-related nonkinase inhibits vascular smooth muscle cell invasion by focal adhesion targeting, tyrosine 168 phosphorylation, and competition for p130(Cas) binding. Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2432-40. doi:, 10.1161/ATVBAHA.111.235549. PMID:21852560 doi:10.1161/ATVBAHA.111.235549
↑ Chu M, Iyengar R, Koshman YE, Kim T, Russell B, Martin JL, Heroux AL, Robia SL, Samarel AM. Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy. Cardiovasc Res. 2011 Dec 1;92(3):409-19. doi: 10.1093/cvr/cvr247. Epub 2011 Sep, 21. PMID:21937583 doi:10.1093/cvr/cvr247
↑ Dao P, Jarray R, Smith N, Lepelletier Y, Coq JL, Lietha D, Hadj-Slimane R, Herbeuval JP, Garbay C, Raynaud F, Chen H. Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities. Cancer Lett. 2014 Mar 19. pii: S0304-3835(14)00152-9. doi:, 10.1016/j.canlet.2014.03.007. PMID:24657306 doi:http://dx.doi.org/10.1016/j.canlet.2014.03.007

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c7t"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4c7t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C7T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C7T FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5RI:N-METHYL-2-[[4-[(3,4,5-TRIMETHOXYPHENYL)AMINO]-1,3,5-TRIAZIN-2-YL]AMINO]BENZAMIDE'>5RI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5RI:N-METHYL-2-[[4-[(3,4,5-TRIMETHOXYPHENYL)AMINO]-1,3,5-TRIAZIN-2-YL]AMINO]BENZAMIDE'>5RI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c7t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c7t RCSB], [http://www.ebi.ac.uk/pdbsum/4c7t 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=4c7t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c7t RCSB], [http://www.ebi.ac.uk/pdbsum/4c7t PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/FAK1_CHICK FAK1_CHICK]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development, embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), ephrin receptors, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Regulates P53/TP53 activity and stability. Phosphorylates SRC; this increases SRC kinase activity. Isoform 2 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling.<ref>PMID:15494733</ref> <ref>PMID:15494734</ref> <ref>PMID:15494732</ref> <ref>PMID:20705914</ref> <ref>PMID:21852560</ref> <ref>PMID:21937583</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 13: / Line 15: @@
 Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities.,Dao P, Jarray R, Smith N, Lepelletier Y, Coq JL, Lietha D, Hadj-Slimane R, Herbeuval JP, Garbay C, Raynaud F, Chen H Cancer Lett. 2014 Mar 19. pii: S0304-3835(14)00152-9. doi:, 10.1016/j.canlet.2014.03.007. PMID:24657306<ref>PMID:24657306</ref>
-From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 == References ==
@@ Line 21: / Line 23: @@
 [[Category: Chick]]
 [[Category: Non-specific protein-tyrosine kinase]]
-[[Category: Coq, J Le.]]
+[[Category: Coq, J Le]]
-[[Category: Lietha, D.]]
+[[Category: Lietha, D]]
 [[Category: Atp-binding]]
 [[Category: Integrin signaling]]
 [[Category: Kinase inhibitor]]
 [[Category: Transferase]]

4c7t

From Proteopedia

Revision as of 22:44, 25 December 2014

Focal Adhesion Kinase catalytic domain in complex with a diarylamino- 1,3,5-triazine inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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