Description

Phosphatidylinositol 3-kinase-Akt signaling pathway plays a crucial role in many important cellular processes. The PI3K generally referenced is the class IA lipid kinase acting downstream of receptor tyrosine kinases. Phosphotyrosine residues on activated receptors or receptor-associated adaptors recruit the regulatory subunit of PI3K to the membrane where the catalytic subunit phosphorylates the 3’ position of the inositol ring of PIP2 to generate PIP3. One or both SH2 (src homology 2) domains of the regulatory subunit may be used in the recruiting event. PIP3 can then recruit to the membrane proteins with phospholipid-binding PH (plekstrin homology) domains, particularly Pdpk1 and Akt. Pdpk1 phosphorylates a threonine in the kinase domain of Akt (T308 in Akt1). Phosphorylation of a serine in the regulatory region (S473 in Akt1) is required for full activation of Akt but the identity of this second kinase, despite a number of proposals, is still elusive. Activated Akts (Akt1, Akt2, Akt3) translocate to the cytoplasm or the nucleus where they phosphorylate more than 70 substrates identified so far. Class IA enzymes are heterodimers of one of three p110 catalytic subunits (a, b or d) and one of the p50-p55/p85 family of regulatory subunits. Class IB enzymes, composed of p110g catalytic subunit and p84 or p101 regulatory subunits, couple to G-protein coupled receptors and are activated by free Gbg subunits of Gai proteins. The catalytic subunits of class I enzymes have Ras binding domains, but so far, an interaction with Ras has been shown for the p110g subunit of class IB. PI3K-Akt activity is inhibited by phosphatases, particularly Pten which dephosphorylates PIP3 to PIP2. Deregulated activation of the pathway either through mutation in the catalytic subunit of PI3K or in Pten has been linked to various forms of cancer. The diagram depicts a generic PI3KIA-Akt pathway.

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Abbreviations
PI3K – phosphatidylinositol 3-kinase
p50-p55/p85  - regulatory subunit of PI3K class IA
p84/p101-regulatory subunit of PI3K class IB
p110 - catalytic subunit of PI3K class I
Pdpk1 – phosphoinosite dependent protein kinase-1
Akt – thymoma viral proto-oncogene
Pten  - phosphatase and tensin homolog
PIP2 – phosphatidylinositol (4,5)-bisphosphate
PIP3 – phosphatidylinositol (3,4,5)-trisphosphate

References
PMID:17052169, 17322919, 17641274, 15505410 16847462, 17979625

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