Biochemical and biological characterization of tumor-associated mutations of p110alpha.
Signaling by class I phosphatidylinositol 3-kinase (PI3K) controls cell growth, replication, motility, and metabolism. The PI3K pathway commonly shows gain of function in cancer. Two small GTPases, Rheb (Ras homolog enriched in brain) and Ras (rat sarcoma viral oncogene), play important roles in PI3K signaling. Rheb activates the TOR (target of rapamycin) kinase in a GTP-dependent manner; it links TOR to upstream signaling components, including the tuberous sclerosis complex (TSC) and Akt (homolog of the Akt8 murine lymphoma viral oncoprotein). Constitutively active, GTP-bound Rheb is oncogenic in cell culture, and activity that requires farnesylation. Ras activates PI3K by recruitment to the plasma membrane and possibly by inducing a conformational change in the catalytic subunit p110 of PI3K. In return, Ras signaling through the MAP kinase (MAPK) pathway is activated by PIP(3), the product of PI3K. Loss of Ras function can interfere with PI3K signaling. Various lines of evidence suggest complementary roles for PI3K and MAPK signaling in oncogenesis.
Denley
Adam
A
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Gymnopoulos
Marco
M
Hart
Jonathan R
JR
Jiang
Hao
H
Zhao
Li
L
Vogt
Peter K
PK
D000818:Animals; D002471:Cell Transformation, Neoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology*; D009479:Neuropeptides / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction
D009479:Neuropeptides; D018129:Phosphatidylinositol Phosphates; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D020559:Monomeric GTP-Binding Proteins