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Cancer Cell. 2002 Mar;1(2):181-91.

Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit.

Author information

1
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. tchan@lac.jci.tju.edu

Abstract

Phosphoinositide 3-kinase (PI3K) type IA is a heterodimer of a catalytic subunit, p110, and a regulatory subunit, p85. Here we show that p85 contains a GTPase-responsive domain and an inhibitory domain, which together form a molecular switch that regulates PI3K. H-Ras and Rac1 activate PI3K by targeting the GTPase-responsive domain. The stimulatory effect of these molecules, however, is blocked by the inhibitory domain, which functions by binding to tyrosine-phosphorylated molecules and is neutralized by tyrosine phosphorylation. The complementary effects of tyrosine kinases and small GTPases on the p85 molecular switch result in synergy between these two classes of molecules toward the activation of the PI3K/Akt pathway.

PMID:
12086876
DOI:
10.1016/s1535-6108(02)00033-8
[Indexed for MEDLINE]
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