PMID- 12955089
OWN - NLM
STAT- MEDLINE
DCOM- 20031007
LR  - 20191210
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 22
IP  - 38
DP  - 2003 Sep 4
TI  - EGF receptor mediates adhesion-dependent activation of the Rac GTPase: a role for 
      phosphatidylinositol 3-kinase and Vav2.
PG  - 6100-6
AB  - Organization of the actin cytoskeleton in eucaryotic cells is controlled by small 
      GTPases of the Rho family. Rac becomes activated by growth factor stimulation and 
      integrin-mediated cell adhesion to extracellular matrix and is known to have a 
      crucial role in lamellipodia formation, cell spreading and migration. At present, 
      the intracellular pathways that connect cell surface receptors to Rac activation 
      are poorly characterized. It has been reported previously that integrin-mediated 
      cell attachment induces activation of the EGF receptor (EGFR) in the absence of 
      EGF. We demonstrate here that this activation is instrumental for 
      integrin-dependent Rac activation. Thus, we found that cells in which EGFR 
      activity had been inhibited failed to spread and form lamellipodia on 
      fibronectin. Failure to spread coincided with inhibition of adhesion-induced GTP 
      loading of Rac and also with inhibition of the phosphatidylinositol 3-kinase (PI 
      3-kinase)/Akt pathway. Subsequent studies demonstrated that an activated form of 
      PI 3-kinase restored Rac GTP loading in the presence of EGFR inhibition, while a 
      dominant-negative form of PI 3-kinase blocked Rac GTP loading in 
      fibronectin-adherent cells. Our further functional studies identified Vav2, a 
      known exchange factor for Rac, as a crucial downstream component in EGFR- and PI 
      3-kinase-dependent Rac activation upon integrin-mediated cell adhesion. Our 
      results provide a mechanistic insight into integrin-dependent Rac activation, and 
      identify a novel role for EGFR, PI 3-kinase and Vav2 in this pathway.
FAU - Marcoux, Nathaly
AU  - Marcoux N
AD  - Cancer Research Center, The Burnham Institute, 10901 N Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Vuori, Kristiina
AU  - Vuori K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Actins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-vav)
RN  - 0 (Quinazolines)
RN  - 0 (Tyrphostins)
RN  - 0 (VAV2 protein, human)
RN  - 170449-18-0 (RTKI cpd)
RN  - 42HK56048U (Tyrosine)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
SB  - IM
MH  - Actins/metabolism/ultrastructure
MH  - Animals
MH  - COS Cells
MH  - Cell Adhesion/*physiology
MH  - Cells, Cultured
MH  - Cytoskeleton/metabolism/ultrastructure
MH  - Enzyme Activation/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - ErbB Receptors/antagonists & inhibitors/genetics/*metabolism
MH  - Focal Adhesion Kinase 1
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Guanosine Triphosphate/metabolism
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Mitogen-Activated Protein Kinases/drug effects/metabolism
MH  - Oncogene Proteins/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Proto-Oncogene Proteins c-vav
MH  - Quinazolines
MH  - Tyrosine
MH  - Tyrphostins/pharmacology
MH  - rac GTP-Binding Proteins/genetics/*metabolism
EDAT- 2003/09/05 05:00
MHDA- 2003/10/08 05:00
CRDT- 2003/09/05 05:00
PHST- 2003/09/05 05:00 [pubmed]
PHST- 2003/10/08 05:00 [medline]
PHST- 2003/09/05 05:00 [entrez]
AID - 1206712 [pii]
AID - 10.1038/sj.onc.1206712 [doi]
PST - ppublish
SO  - Oncogene. 2003 Sep 4;22(38):6100-6. doi: 10.1038/sj.onc.1206712.