PIK3CA (PI3Kα)
PIK3CA encodes the p110α catalytic subunit of phosphoinositide 3-kinase α, a lipid kinase that signals downstream of growth-factor and insulin receptors.
Function
PI3Kα is recruited to activated receptor tyrosine kinases by its p85 regulatory subunit and phosphorylates the membrane lipid PIP2 into PIP3. PIP3 docks AKT and PDK1 at the membrane, where AKT is activated; AKT then drives glucose uptake, protein synthesis (through mTOR), and survival. The lipid product is opposed by PTEN, the phosphatase that converts PIP3 back to PIP2, so the pathway’s output is a balance between PI3K and PTEN activity.
In cancer
PIK3CA is among the most frequently mutated oncogenes in human cancer - activating mutations occur in roughly a third of breast cancers, a quarter of endometrial cancers, and large fractions of colorectal cancers. The mutations (hotspots E545K and H1047R) release the catalytic subunit from its regulatory restraint. PI3K pathway activation also drives resistance to endocrine therapy in breast cancer, and PI3K inhibitors (alpelisib) are approved for PIK3CA-mutant breast cancer. Germline PIK3CA mutations cause PROS, the overgrowth syndromes.
Notes
- Human gene symbol: PIK3CA; UniProt P42336; 1,068 amino acids; lipid kinase, class IA PI3K catalytic subunit.