PMID- 7820549
OWN - NLM
STAT- MEDLINE
DCOM- 19950216
LR  - 20231120
IS  - 0960-9822 (Print)
IS  - 0960-9822 (Linking)
VI  - 4
IP  - 9
DP  - 1994 Sep 1
TI  - The activation of phosphatidylinositol 3-kinase by Ras.
PG  - 798-806
AB  - BACKGROUND: Activation of the mammalian phosphatidylinositol 3-kinase complex can 
      play a critical role in transducing growth factor responses. The lipid kinase 
      complex, which is made up of p85 alpha and p110 alpha regulatory and catalytic 
      subunits, becomes associated with a number of activated receptor protein tyrosine 
      kinases, but the mechanism of its activation has not yet been defined. Recent 
      evidence indicates that Ras can bind to the p85 alpha/p110 alpha complex. We 
      describe here the functional regulation of the mammalian phosphatidylinositol 
      3-kinase complex by Ras. RESULTS: Expression of p110 alpha, the catalytic subunit 
      of phosphatidylinositol 3-kinase, in the fission yeast, Schizosaccharomyces 
      pombe, has been used to demonstrate an inhibitory effect of p85 alpha on p110 
      alpha activity in intact cells; inhibition did not result from a decrease in p110 
      alpha expression. In this cellular context, we have investigated the effect of a 
      constitutively active mutant of Ras, v-Ras, either on p85 alpha or p110 
      alpha-alone, or on the p85 alpha/p110 alpha complex. In the presence of the p85 
      alpha/p110 alpha complex, v-Ras suppressed cell growth, but an effector-domain 
      mutant of v-Ras did not. The growth-suppressive effect of v-Ras was not seen for 
      any other combination of expressed proteins. The phenotype induced by v-Ras was 
      consistent with activation of the p85 alpha/p110 alpha complex: it was sensitive 
      to the phosphatidylinositol 3-kinase inhibitor, wortmannin, and the cells 
      accumulated 3-phosphorylated polyphosphoinositides. Activation of purified p85 
      alpha/p110 alpha by purified recombinant Ras in vitro was also demonstrated. 
      CONCLUSIONS: The phosphatidylinositol 3-kinase complex, p85 alpha/p110 alpha, 
      shows a suppressed catalytic function in vivo when compared with free p110 alpha. 
      This complex can, however, be activated by Ras. We suggest that the 
      phosphatidylinositol 3-kinase p85 alpha/p110 alpha complex is a downstream 
      effector of Ras.
FAU - Kodaki, T
AU  - Kodaki T
AD  - Protein Phosphorylation Laboratory, Imperial Cancer Research Fund, London, UK.
FAU - Woscholski, R
AU  - Woscholski R
FAU - Hallberg, B
AU  - Hallberg B
FAU - Rodriguez-Viciana, P
AU  - Rodriguez-Viciana P
FAU - Downward, J
AU  - Downward J
FAU - Parker, P J
AU  - Parker PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
GS  - v-Ras
MH  - Animals
MH  - Cattle
MH  - Enzyme Activation/drug effects
MH  - Gene Expression
MH  - In Vitro Techniques
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphotransferases (Alcohol Group Acceptor)/chemistry/genetics/*metabolism
MH  - Protein Conformation
MH  - Schizosaccharomyces/enzymology/genetics
MH  - Signal Transduction
MH  - ras Proteins/genetics/*pharmacology
EDAT- 1994/09/01 00:00
MHDA- 1994/09/01 00:01
CRDT- 1994/09/01 00:00
PHST- 1994/09/01 00:00 [pubmed]
PHST- 1994/09/01 00:01 [medline]
PHST- 1994/09/01 00:00 [entrez]
AID - S0960-9822(00)00177-9 [pii]
AID - 10.1016/s0960-9822(00)00177-9 [doi]
PST - ppublish
SO  - Curr Biol. 1994 Sep 1;4(9):798-806. doi: 10.1016/s0960-9822(00)00177-9.