Anti-apoptotic role of caspase-cleaved GAB1 adaptor protein in hepatocyte growth factor/scatter factor-MET receptor protein signaling.
The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling.
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Arnaud
A
Le Goff
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France; Faculty of Life Sciences, C2222 Michael Smith Building, University of Manchester, Manchester, United Kingdom.
Zongling
Z
Ji
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Bérénice
B
Leclercq
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Roland P
RP
Bourette
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Alexandra
A
Mougel
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Cateline
C
Guerardel
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Yvan
Y
de Launoit
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Jérôme
J
Vicogne
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
Gautier
G
Goormachtigh
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France. Electronic address: veronique.fafeur@ibl.fr.
Véronique
V
Fafeur
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation / Q000502:physiology; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases