Pik3ca Gene

PIK3CA is the acronym for phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha.

Phosphoinositide 3-kinases also known as PI-3-kinases (PI3K), are one of the most frequently dysregulated signaling pathways in human cancers and are associated with many cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PIK3CA is an integral component of the PI3K signaling pathway.

PIK3CA has long been described as an oncogene. The kinase has two major hotspots for activating mutations, the 542/545 region of the helical domain and the 1047 region of the kinase domain. A pseudogene of this gene has been defined on chromosome 22.

Determination of the mutation status of the PIK3CA gene is important, among other things, in the treatment of patients with:

• Colorectal carcinoma (CRC)
• Breast carcinoma
• Lung carcinoma
• Acrolentiginous melanoma (ALM).

List of diseases with detected germline and somatic mutations in the PIK3CA gene:

• Disease-causing germline mutation(s): Cowden syndrome
• Disease-causing somatic mutation(s): CLOVE(S) syndrome
• Disease-causing somatic mutation(s): Hemihyperplasia-multiple lipomatosis syndrome
• Disease-causing somatic mutation(s): Hemimegalencephaly
• Disease-causing somatic mutation(s): Hepatocellular carcinoma, adult-onset
• Disease-causing somatic mutation(s): Macrodactyly of fingers, unilateral
• Disease-causing somatic mutation(s): Macrodactyly of toes, unilateral Hemihyperplasia-multiple lipomatosis syndrome
• Disease-causing somatic mutation(s): Segmental-progressive tall stature syndrome with fibroadipose hyperplasia

• PIK3CA-related overgrowth spectrum" (PROS). This entity includes the "megalencephaly-capillary malformation-polymicrogyria" (MCAP) syndrome, in which the asymmetric growth disorder is usually present from birth and continues to increase during childhood. Affected children often exhibit macrocephaly and capillary vascular malformations (nevus flammeus) as well as marbled skin. The detection of PIK3CA mutations in the mosaic is usually not possible in the blood, but only in DNA from affected tissue. Skin biopsies are particularly suitable.

The mutation frequency of PIK3CA is approximately 30% in breast carcinoma, 10-30% in colorectal carcinoma and 1-3% in lung carcinoma . In non-small cell lung cancer(NSCLC), PIK3CA mutations can occur together with mutations in the EGFR gene.

PI 3-kinases (phosphoinositide 3-kinases, PI 3-Ks) are a family of lipid kinases that are able to phosphorylate the 3'OH of the inositol ring of phosphoinositides. They are responsible for coordinating a variety of cell functions, including proliferation and survival.

The phosphatidylinositol 3-kinase encoded by the PIK3CA gene consists of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene is the catalytic subunit that utilizes ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. The PIK3CA kinase is an integral part of the PI3K signaling pathway and has long been described as an oncogene with two major hotspots for activating mutations: the 542/545 region of the helical domain and the 1047 region of the kinase domain.

Phosphatidylinositiol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate are phosphorylated with ATP consumption to generate PIP3 (phosphatidylinositol-3,4,5-trisphosphate). PIP3 plays a key role in the activation of signaling cascades involved in cell growth, survival, proliferation, motility and morphology.

Phosphoinositide 3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (Meier TI et al. 2004; Buchanan CM et al. 2013). The kinase uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to form phosphatidylinositol 3,4,5-trisphosphate (PIP3) (Maheshwari S et al. 2017). PIP3 plays a key role by adapting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, thus activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. It participates in cellular signaling in response to various growth factors.

Furthermore, the enzyme is involved in the activation of AKT1 after stimulation by receptor tyrosine kinase ligands such as EGF, insulin, IGF1, VEGFA and PDGF. It is involved in signaling via insulin receptor substrate proteins (IRS) and is essential for endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity.

PI3K is required for the development of the lymphatic vasculature, possibly through binding to RAS and activation by EGF and FGF2. The enzyme is involved in cardiomyogenesis in embryonic stem cells via an AKT1 pathway and in vasculogenesis in embryonic stem cells via the PDK1 and protein kinase C pathways.

In addition to its lipid kinase activity, it exhibits serine protein kinase activity leading to autophosphorylation of the regulatory subunit p85alpha as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (Maheshwari S et al. 2017). Plays a role in the positive regulation of phagocytosis and pinocytosis .

PIK3CA and its interaction with the AKT and mTOR signaling pathways are the subject of extensive research and development. PI3K inhibition has had some limited success in recent clinical trials. While monotherapies appear to be limited in their potential, there has been recent interest in pursuing PI3K inhibition as part of combination therapy with inhibition partners such as TKIs, MEK inhibitors, PARP inhibitors and, in breast cancer, aromatase inhibitors.

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