Phosphatidylinositol 3-kinase regulatory subunit beta

Function

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. Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity).

Classification

Family (Pfam)

PF16454 PI3K_P85_iSH2, PF00620 RhoGAP, PF00017 SH2

InterPro

PI3K_P85_iSH2, PI3K_p85beta_SH3, PI3kinase_P85_cSH2, PI3kinase_P85_nSH2, Rho_GTPase_activation_prot, RhoGAP_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain

Functional cluster

Nucleic Acid Metabolism & Repair Enzymes

Experimental structures · PDB · 8

• 2KT1 NMR
• 2XS6 X-ray 2.09A
• 3MTT X-ray 3.30A
• 3O5Z X-ray 2.01A
• 6OX7 X-ray 2.75A
• 6U28 X-ray 2.95A
• 7RCH X-ray 3.10A
• 7RNU X-ray 1.45A

A predicted model is available from AlphaFold.

Gene Ontology · 24

• GO:0005829 cytosol
• GO:0005925 focal adhesion
• GO:0005634 nucleus
• GO:0005943 phosphatidylinositol 3-kinase complex, class IA
• GO:0046935 1-phosphatidylinositol-3-kinase regulator activity
• GO:0005096 GTPase activator activity
• GO:0036312 phosphatidylinositol 3-kinase regulatory subunit binding
• GO:0001784 phosphotyrosine residue binding
• GO:0046982 protein heterodimerization activity
• GO:0019903 protein phosphatase binding
• GO:0030971 receptor tyrosine kinase binding
• GO:0030183 B cell differentiation
• GO:0032869 cellular response to insulin stimulus
• GO:0006955 immune response
• GO:0008286 insulin receptor signaling pathway
• GO:0001678 intracellular glucose homeostasis
• GO:0043409 negative regulation of MAPK cascade
• GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:0042307 positive regulation of protein import into nucleus
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0015031 protein transport
• GO:0010506 regulation of autophagy
• GO:0034976 response to endoplasmic reticulum stress
• GO:0030217 T cell differentiation

Disease associations

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 MONDO:0011313

Drugs targeting this protein · 23

• PF-04691502 inhibitor
• OMIPALISIB inhibitor
• IZORLISIB inhibitor
• DACTOLISIB inhibitor
• APITOLISIB inhibitor
• BUPARLISIB inhibitor
• AZD-6482 inhibitor
• RECILISIB inhibitor
• SF-1126 inhibitor
• TASELISIB inhibitor
• PILARALISIB inhibitor
• VS-5584 inhibitor
• GSK-1059615 inhibitor
• BGT-226 inhibitor
• VOXTALISIB inhibitor
• PAXALISIB inhibitor
• SONOLISIB inhibitor
• SAMOTOLISIB inhibitor
• PUQUITINIB MESYLATE DIHYDRATE inhibitor
• PANULISIB inhibitor
• PICTILISIB inhibitor
• ZSTK-474 inhibitor
• GEDATOLISIB inhibitor

Related proteins · sequence + function similarity

• Phosphatidylinositol 3-kinase regulatory subunit beta 0.99
• Phosphatidylinositol 3-kinase regulatory subunit beta 0.98
• Phosphatidylinositol 3-kinase regulatory subunit beta 0.98
• Protein TAMALIN 0.65
• Serine/threonine-protein kinase N1 0.65
• Rho guanine nucleotide exchange factor 2 0.64
• Serine/threonine-protein kinase N1 0.64
• Rho guanine nucleotide exchange factor 2 0.64
• Sterile alpha motif domain-containing protein 5 0.63
• General receptor for phosphoinositides 1-associated scaffold protein 0.63
• Sterile alpha motif domain-containing protein 5 0.62
• Serine/threonine-protein kinase N1 0.62

Co-cited proteins · studied together in the literature

• Phosphatidylinositol 3-kinase regulatory subunit beta 1 shared papers
• RAC-gamma serine/threonine-protein kinase 2 shared papers
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 1 shared papers
• F-box/LRR-repeat protein 2 1 shared papers
• Tyrosine-protein phosphatase non-receptor type 13 1 shared papers
• Receptor-type tyrosine-protein phosphatase eta 1 shared papers
• Phosphatidylinositol 3-kinase regulatory subunit alpha 3 shared papers
• Vascular endothelial growth factor receptor 1 1 shared papers
• Tyrosine-protein phosphatase non-receptor type 11 2 shared papers
• SH2/SH3 adapter protein NCK1 1 shared papers
• 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 2 shared papers
• Piwi-like protein 2 1 shared papers

Literature · 21 cited papers

• Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK. Oncotarget · 2017
• De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia. Eur. J. Hum. Genet. · 2016
• Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. Lancet Neurol. · 2015
• N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
• AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. Clin. Genet. · 2014
• FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade. Nat. Cell Biol. · 2013
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. · 2012
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. · 2010
• Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
• Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
• … and 9 more in the literature graph