Protein / target
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Protein at a glance
Biological role
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Primary system
Cardiovascular system
Strongest disease association
megalencephaly-capillary malformation-polymicrogyria syndrome
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
4 approved · 27 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). 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 (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity)
Domains and Gene Ontology detail (62)Hide
Domains & features
Gene Ontology
- Ccytoplasm
- Ccytosol
- Cintercalated disc
- Clamellipodium
- Cperinuclear region of cytoplasm
- Cphosphatidylinositol 3-kinase complex
- Cphosphatidylinositol 3-kinase complex, class IA
- Cphosphatidylinositol 3-kinase complex, class IB
- Cplasma membrane
- F1-phosphatidylinositol-3-kinase activity
- F1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
- F1-phosphatidylinositol-4-phosphate 3-kinase activity
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Kinase signalling
- ·Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosph…
- ·1-phosphatidylinositol-3-kinase activity
- ·1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
- ·1-phosphatidylinositol-4-phosphate 3-kinase activity
Immune signalling
- ·T cell receptor signaling pathway
- ·Interleukin-3, Interleukin-5 and GM-CSF signaling
Muscle contraction
- ·cardiac muscle contraction
- ·negative regulation of actin filament depolymerization
- ·regulation of actin filament organization
Transcriptional regulation
- ·negative regulation of gene expression
Haemostasis
- ·platelet activation
View underlying pathways (25)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
PI3-kinase p110-alpha subunit inhibitor
Appears in clinical studies involving breast cancer, breast neoplasm, neoplasm, breast carcinoma
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 1,791 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 32 total
endometrial carcinoma · breast cancer · lymphoma
colorectal cancer · neoplasm · neoplasm
head and neck cancer · head and neck squamous cell carcinoma · hepatocellular carcinoma
follicular lymphoma · non-Hodgkin lymphoma · neoplasm
colorectal cancer · glioblastoma · endometrial cancer
radiation injury
breast cancer · non-Hodgkin lymphoma · non-small cell lung carcinoma
Respiratory tract infection · breast cancer · endometrial carcinoma
prostate cancer · non-small cell lung carcinoma · endometrial cancer
Tractability
Safety liabilities
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through a drug that targets this protein, so each event is news about that drug rather than about the protein directly.
- CHMP positive opinion
CHMP positive opinion: Vijoice (EMA)
- Label change
Label change: ALPELISIB (NDA215039)
- Indication expanded
Indication expansion: ALPELISIB (NDA215039)
- New publicationIncidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer.
- Label change
Label change: ALPELISIB (NDA215039)
- Regulatory approval
Approval: ALPELISIB (NDA215039)
- New publicationAlpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.
- Regulatory approval
Approval: Piqray (EMA)
- New publicationFrequency and spectrum of PIK3CA somatic mutations in breast cancer.
- New publicationAlpelisib for <i>PIK3CA</i>-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.