| Structural highlights
Function
[PK3CB_MOUSE] 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. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.[1] [2] [3] [4] [5] [6] [P85B_MOUSE] Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates 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. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy.[UniProtKB:O00459]
Publication Abstract from PubMed
Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110beta/p85beta complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit. Mutagenesis of a cSH2 contact residue activates downstream signaling in cells. This inhibitory contact ties up the C-terminal region of the p110beta catalytic subunit, which is essential for lipid kinase activity. In vitro, p110beta basal activity is tightly restrained by contacts with three p85 domains: the cSH2, nSH2, and iSH2. RTK phosphopeptides relieve inhibition by nSH2 and cSH2 using completely different mechanisms. The binding site for the RTK's pYXXM motif is exposed on the cSH2, requiring an extended RTK motif to reach and disrupt the inhibitory contact with p110beta. This contrasts with the nSH2 where the pY-binding site itself forms the inhibitory contact. This establishes an unusual mechanism by which p85 SH2 domains contribute to RTK signaling specificities.
Structure of Lipid Kinase p110beta/p85beta Elucidates an Unusual SH2-Domain-Mediated Inhibitory Mechanism.,Zhang X, Vadas O, Perisic O, Anderson KE, Clark J, Hawkins PT, Stephens LR, Williams RL Mol Cell. 2011 Mar 4;41(5):567-78. PMID:21362552[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25. PMID:18594509 doi:http://dx.doi.org/10.1038/nature07091
- ↑ Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8292-7. doi:, 10.1073/pnas.0707761105. Epub 2008 Jun 10. PMID:18544649 doi:http://dx.doi.org/10.1073/pnas.0707761105
- ↑ Canobbio I, Stefanini L, Cipolla L, Ciraolo E, Gruppi C, Balduini C, Hirsch E, Torti M. Genetic evidence for a predominant role of PI3Kbeta catalytic activity in ITAM- and integrin-mediated signaling in platelets. Blood. 2009 Sep 3;114(10):2193-6. doi: 10.1182/blood-2009-03-208074. Epub 2009, Jun 10. PMID:19515725 doi:http://dx.doi.org/10.1182/blood-2009-03-208074
- ↑ Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, Vanhaesebroeck B, Payrastre B, Gratacap MP. Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood. 2010 Mar 11;115(10):2008-13. doi: 10.1182/blood-2009-04-217224. Epub 2010 , Jan 11. PMID:20065293 doi:http://dx.doi.org/10.1182/blood-2009-04-217224
- ↑ Schoenwaelder SM, Ono A, Nesbitt WS, Lim J, Jarman K, Jackson SP. Phosphoinositide 3-kinase p110 beta regulates integrin alpha IIb beta 3 avidity and the cellular transmission of contractile forces. J Biol Chem. 2010 Jan 22;285(4):2886-96. doi: 10.1074/jbc.M109.029132. Epub 2009 , Nov 23. PMID:19940148 doi:http://dx.doi.org/10.1074/jbc.M109.029132
- ↑ Dou Z, Chattopadhyay M, Pan JA, Guerriero JL, Jiang YP, Ballou LM, Yue Z, Lin RZ, Zong WX. The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. J Cell Biol. 2010 Nov 15;191(4):827-43. doi: 10.1083/jcb.201006056. Epub 2010 Nov, 8. PMID:21059846 doi:http://dx.doi.org/10.1083/jcb.201006056
- ↑ Zhang X, Vadas O, Perisic O, Anderson KE, Clark J, Hawkins PT, Stephens LR, Williams RL. Structure of Lipid Kinase p110beta/p85beta Elucidates an Unusual SH2-Domain-Mediated Inhibitory Mechanism. Mol Cell. 2011 Mar 4;41(5):567-78. PMID:21362552 doi:10.1016/j.molcel.2011.01.026
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