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PI3Ks

Thursday 4 December 2003

PI3Ks, PI3-kinases, phosphatidylinositol 3-kinases, PI3 kinases, PI3K; PIK3s; Phosphoinositide 3-kinase

WKP

Definition: Phosphoinositide 3-kinases (PI 3-kinases or PI3Ks) are a family of related enzymes that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns). They are also known as phosphatidylinositol-3-kinases (PI3Ks or PIK3s).

Members of the PIK (phosphatidylinositol kinase)-related kinase family (PIKs) are high molecular weight kinases involved in cell cycle progression, DNA recombination, and the detection of DNA damage

Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids implicated in the regulation of cell growth, proliferation, survival, differentiation, and cytoskeletal changes.

Receptor-regulated class I phosphoinositide 3-kinases (PI3Ks) phosphorylate the membrane lipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to PtdIns(3,4,5)P3, which in turn recruits and activates cytosolic effectors involved in proliferation, survival, or chemotaxis.

Subunits

PIK3CA PIK3CB PIK3CD PIK3CG
PIK3R1 PIK3R2 PIK3R3 PIK3R4 PIK3R5

Function

One of the best characterized targets of PI3K lipids are the protein kinases B (PKBs) or AKTs (AKT1 and AKT2).

AKT2 (MIM.164731) is the isoform of AKT 1 and is enriched in insulin-responsive tissues and has been implicated in the metabolic actions of the hormone.

In quiescent cells, AKT1 resides in the cytosol in a low-activity conformation. Upon cellular stimulation, AKT1 is activated through recruitment to cellular membranes by PI3K lipids and by phosphorylation by 3-prime phosphoinositide-dependent kinase-1 (PDPK1) (MIM.605213).

PTEN

PTEN suppresses phosphoinositol-3-kinase (PI3K) signaling, thereby down-regulating downstream mediators, including the oncogenic serine-threonine kinase AKT1, which in turn regulates the mTOR (mammalian target of rapamycin) growth pathway.

Pathology

- PI3K-mutated colorectal adenocarcinoma

PI3Ks and leukocyte motility

Morphologic polarity is necessary for the motility of mammalian cells. In leukocytes responding to a chemoattractant, this polarity is regulated by activities of small Rho guanosine triphosphatases (Rho GTPases) and the phosphoinositide 3-kinases (PI3Ks). In neutrophils, lipid products of PI3Ks appear to regulate activation of Rho GTPases, are required for cell motility and accumulate asymmetrically to the plasma membrane at the leading edge of polarized cells.

By spatially regulating Rho GTPases and organizing the leading edge of the cell, PI3Ks and their lipid products could play pivotal roles not only in establishing leukocyte polarity but also as compass molecules that tell the cell where to crawl.

See also

- AKTs: AKT1 and AKT2

References

- Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006 Aug;7(8):606-19. PMID: 16847462

- Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. PMID: 16341064

- Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005 Dec;5(12):921-9. PMID: 16341083

- Samuels Y, Zhu J, Lengauer C. Inhibiting phosphoinositide 3-kinases. Cancer Biol Ther. 2005 May;4(5):546-7. PMID: 15908801

- Kharas MG, Fruman DA. ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors. Cancer Res. 2005 Mar 15;65(6):2047-53. PMID: 15781610

- Abraham RT. PI 3-kinase related kinases: ’big’ players in stress-induced signaling pathways. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):883-7. PMID: 15279773

- Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004 Apr 19;23(18):3151-71. PMID: 15094765

- Weaver SA, Ward SG. Phosphoinositide 3-kinases in the gut: a link between inflammation and cancer? Trends Mol Med. 2001 Oct;7(10):455-62. PMID: 11597520

- Rickert P, Weiner OD, Wang F, Bourne HR, Servant G. Leukocytes navigate by compass: roles of PI3Kgamma and its lipid products. Trends Cell Biol. 2000 Nov;10(11):466-73. PMID: 11050418

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