Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion.
FGFR2-expressing human cancer cells with low concentrations of the adaptor protein Grb2 show high prevalence for metastatic outcome. In nonstimulated cells, the SH3 domain (and not the SH2 domains) of Plcγ1 directly competes for a binding site at the very C terminus of FGFR2 with the C-terminal SH3 domain of Grb2. Reduction of Grb2 concentration permits Plcγ1 access to the receptor. Recruitment of Plcγ1 in this way is sufficient to upregulate phospholipase activity. This results in elevated phosphatidylinositol 4,5-bisphosphate turnover and intracellular calcium levels, thus leading to increased cell motility and promotion of cell-invasive behavior in the absence of extracellular receptor stimulation. Therefore, metastatic outcome can be dictated by the constitutive competition between Grb2 and Plcγ1 for the phosphorylation-independent binding site on FGFR2.
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Zahra
Z
Timsah
1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. [2] Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Zamal
Z
Ahmed
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Chi-Chuan
CC
Lin
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Fernando A
FA
Melo
1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. [2] Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Loren J
LJ
Stagg
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Paul G
PG
Leonard
Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
Prince
P
Jeyabal
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA.
Jonathan
J
Berrout
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA.
Roger G
RG
O'Neil
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, Houston, Texas, USA.
Mikhail
M
Bogdanov
1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. [2] Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
John E
JE
Ladbury
D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D051380:GRB2 Adaptor Protein / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008957:Models, Genetic; D009361:Neoplasm Invasiveness / Q000235:genetics; D051966:Phospholipase C gamma / Q000378:metabolism / Q000502:physiology*; D010740:Phospholipases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*
D051380:GRB2 Adaptor Protein; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D010740:Phospholipases; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma