Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Function

Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP 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 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. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others. Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).

Classification

Family (Pfam)

PF00454 PI3_PI4_kinase, PF00792 PI3K_C2, PF02192 PI3K_p85B, PF00794 PI3K_rbd, PF00613 PI3Ka

InterPro

ARM-type_fold, C2_domain_sf, Kinase-like_dom_sf, PI3-kinase_alpha_cat, PI3/4_kinase, PI3/4_kinase_cat_dom, PI3/4_kinase_cat_sf, PI3/4_kinase_CS, PI3K-type_C2_dom, PI3K_ABD, PI3K_accessory_dom, PI3K_accessory_sf, PI3K_Ras-bd_dom, Ubiquitin-like_domsf

Functional cluster

Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 120

• 2ENQ NMR
• 2RD0 X-ray 3.05A
• 3HHM X-ray 2.80A
• 3HIZ X-ray 3.30A
• 3ZIM X-ray 2.85A
• 4JPS X-ray 2.20A
• 4L1B X-ray 2.59A
• 4L23 X-ray 2.50A
• 4L2Y X-ray 2.80A
• 4OVU X-ray 2.96A
• 4OVV X-ray 3.50A
• 4TUU X-ray 2.64A
• … and 108 more

A predicted model is available from AlphaFold.

Gene Ontology · 57

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0014704 intercalated disc
• GO:0030027 lamellipodium
• GO:0048471 perinuclear region of cytoplasm
• GO:0005942 phosphatidylinositol 3-kinase complex
• GO:0005943 phosphatidylinositol 3-kinase complex, class IA
• GO:0005944 phosphatidylinositol 3-kinase complex, class IB
• GO:0005886 plasma membrane
• GO:0016303 1-phosphatidylinositol-3-kinase activity
• GO:0046934 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• GO:0035005 1-phosphatidylinositol-4-phosphate 3-kinase activity
• GO:0005524 ATP binding
• GO:0043560 insulin receptor substrate binding
• GO:0030295 protein kinase activator activity
• GO:0106310 protein serine kinase activity
• GO:0004674 protein serine/threonine kinase activity
• GO:0030036 actin cytoskeleton organization
• GO:0001525 angiogenesis
• GO:0043276 anoikis
• GO:0086003 cardiac muscle cell contraction
• GO:0060048 cardiac muscle contraction
• GO:0016477 cell migration
• GO:0071464 cellular response to hydrostatic pressure
• GO:0032869 cellular response to insulin stimulus
• GO:0043542 endothelial cell migration
• GO:0007173 epidermal growth factor receptor signaling pathway
• GO:0008286 insulin receptor signaling pathway
• GO:0048009 insulin-like growth factor receptor signaling pathway
• GO:0030835 negative regulation of actin filament depolymerization
• GO:2000811 negative regulation of anoikis
• GO:0010629 negative regulation of gene expression
• GO:0016242 negative regulation of macroautophagy
• GO:0006909 phagocytosis
• GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:0046854 phosphatidylinositol phosphate biosynthetic process
• GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process
• GO:0048015 phosphatidylinositol-mediated signaling
• GO:0030168 platelet activation
• GO:0010592 positive regulation of lamellipodium assembly
• GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:0045860 positive regulation of protein kinase activity
• GO:1905477 positive regulation of protein localization to membrane
• GO:0048661 positive regulation of smooth muscle cell proliferation
• GO:0032008 positive regulation of TOR signaling
• GO:0110053 regulation of actin filament organization
• GO:0055119 relaxation of cardiac muscle
• GO:0014823 response to activity
• GO:1903544 response to butyrate
• GO:0071548 response to dexamethasone
• GO:0043201 response to L-leucine
• GO:0014870 response to muscle inactivity
• GO:0035994 response to muscle stretch
• GO:0050852 T cell receptor signaling pathway
• GO:0038203 TORC2 signaling
• GO:0038084 vascular endothelial growth factor signaling pathway
• GO:0001944 vasculature development

Disease associations

• hereditary breast carcinoma MONDO:0016419
• colorectal cancer MONDO:0005575
• hepatocellular carcinoma MONDO:0007256
• megalodactyly MONDO:0007962
• ovarian cancer MONDO:0008170
• seborrheic keratosis MONDO:0008420
• megalencephaly-capillary malformation-polymicrogyria syndrome MONDO:0011240
• hemifacial myohyperplasia MONDO:0011723
• CLOVES syndrome MONDO:0013038
• CLAPO syndrome MONDO:0013125
• Cowden syndrome 5 MONDO:0014047
• cerebral cavernous malformation 4 MONDO:0859192

Drugs targeting this protein · 31

• PF-04691502 inhibitor
• OMIPALISIB inhibitor
• PKI-179 inhibitor
• IZORLISIB inhibitor
• DACTOLISIB inhibitor
• APITOLISIB inhibitor
• BUPARLISIB inhibitor
• AZD-6482 inhibitor
• RECILISIB inhibitor
• SF-1126 inhibitor
• TASELISIB inhibitor
• ALPELISIB inhibitor
• COPANLISIB inhibitor
• PILARALISIB inhibitor
• VS-5584 inhibitor
• GSK-1059615 inhibitor
• COPANLISIB HYDROCHLORIDE inhibitor
• BGT-226 inhibitor
• VOXTALISIB inhibitor
• FIMEPINOSTAT inhibitor
• BAY-1082439 inhibitor
• PAXALISIB inhibitor
• SERABELISIB inhibitor
• SONOLISIB inhibitor
• SAMOTOLISIB inhibitor
• PUQUITINIB MESYLATE DIHYDRATE inhibitor
• INAVOLISIB inhibitor
• PANULISIB inhibitor
• PICTILISIB inhibitor
• ZSTK-474 inhibitor
• GEDATOLISIB inhibitor

Related proteins · sequence + function similarity

• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 1.00
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 1.00
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform 1.00
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform 0.95
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform 0.95
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform 0.95
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform 0.90
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform 0.90
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform 0.89
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform 0.83
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform 0.79
• Phosphatidylinositol 3-kinase catalytic subunit type 3 0.76

Co-cited proteins · studied together in the literature

• Phosphatidylinositol 3-kinase regulatory subunit alpha 4 shared papers
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform 2 shared papers
• DCC-interacting protein 13-alpha 1 shared papers
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform 2 shared papers
• Phosphatidylinositol 3-kinase regulatory subunit beta 1 shared papers
• Protein FAM83B 1 shared papers
• RAC-alpha serine/threonine-protein kinase 2 shared papers
• RAC-gamma serine/threonine-protein kinase 1 shared papers
• Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform 1 shared papers
• Forkhead box protein M1 1 shared papers

Literature · 38 cited papers

• Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition. J. Exp. Med. · 2023
• Somatic PIK3CA mutations in sporadic cerebral cavernous malformations. N. Engl. J. Med. · 2021
• PI3K activation is enhanced by FOXM1D binding to p110 and p85 subunits. Signal Transduct. Target. Ther. · 2020
• CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype. Genet. Med. · 2018
• Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase alpha that are critical for catalysis and substrate recognition. J. Biol. Chem. · 2017
• Identification and characterisation of a novel constitutional PIK3CA mutation in a child lacking the typical segmental overgrowth of 'PIK3CA-related overgrowth spectrum' (PROS). Hum. Mutat. · 2016
• Oncogenic mutations of p110alpha isoform of PI 3-kinase upregulate its protein kinase activity. PLoS ONE · 2013
• FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies. Oncotarget · 2013
• Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. · 2013
• Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum. Mol. Genet. · 2013
• De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. · 2012
• Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. · 2012
• … and 26 more in the literature graph