Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit.
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.
Chan
Tung O
TO
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. tchan@lac.jci.tju.edu
Rodeck
Ulrich
U
Chan
Andrew M
AM
Kimmelman
Alec C
AC
Rittenhouse
Susan E
SE
Panayotou
George
G
Tsichlis
Philip N
PN
D016475:3T3 Cells; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006133:Growth Substances / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics
D020558:GTP Phosphohydrolases; D006133:Growth Substances; D016023:Integrins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins