Gab1 mediates hepatocyte growth factor‐stimulated mitogenicity and morphogenesis in multipotent myeloid cells

Abstract

Hepatocyte growth factor (HGF)-stimulated mitogenesis, motogenesis and morphogenesis in various cell types begins with activation of the Met receptor tyrosine kinase and the recruitment of intracellular adaptors and kinase substrates. The adapter protein Gab1 is a critical effector and substrate of activated Met, mediating morphogenesis, among other activities, in epithelial cells. To define its role downstream of Met in hematopoietic cells, Gab1 was expressed in the HGF-responsive, Gab1-negative murine myeloid cell line 32D. Interestingly, the adhesion and motility of Gab1-expressing cells were significantly greater than parental cells, independent of growth factor treatment. Downstream of activated Met, Gab1 expression was specifically associated with rapid Shp-2 recruitment and activation, increased mitogenic potency, suppression of GATA-1 expression and concomitant upregulation of GATA-2 transcription. In addition to enhanced proliferation, continuous culture of Gab1-expressing 32D cells in HGF resulted in cell attachment, filopodia extension and phenotypic changes suggestive of monocytic differentiation. Our results suggest that in myeloid cells, Gab1 is likely to enhance HGF mitogenicity by coupling Met to Shp-2 and GATA-2 expression, thereby potentially contributing to normal myeloid differentiation as well as oncogenic transformation.

MicroRNA‐409‐3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression

“…GAB1 belongs to the Grb2‐associtated binder (Gab) family which are scaffolding adapter molecules involved in transducting key signals that control cell growth and differentiation from multiple receptors such as growth factors, cytokines and antigen receptors . It has been implicated in tumor occurrence, invasion and metastasis, particularly in gastrointestinal tumors . Recent reports have shown that GAB1 promotes tumorigenesis by acting as an “accomplice” of certain oncoproteins or by amplifying the signaling from multiple receptors .…”

Gene expression analysis of mammary tissue during fetal bud formation and growth in two pig breeds – indications of prenatal initiation of postnatal phenotypic differences

“…GAB1 functions as a mediator in growth factor signaling and cytokine receptor, especially in EGF signaling, HGF signaling and Platelet-derived growth factor (PDGF) signaling which stimulates the migration of epithelial, mesenchymal and hematopoietic cells during embryogenesis and branching morphogenesis of epithelial cells. The deficiency of GAB1 results in the lack of ligands, receptors and signaling molecules and develop the organs [30-34]. …”

Acquired Substrate Preference for GAB1 Protein Bestows Transforming Activity to ERBB2 Kinase Lung Cancer Mutants

“…Previous studies have revealed that GAB1 orchestrates signaling from a variety of cell surface receptor kinases such as EGFR (21,30), ERBB2 (18), and c-MET (31,32). GAB1 is phosphorylated by the activated receptor kinases at multiple tyrosine sites and recruits downstream signaling proteins such as SHP2 and PI3K, which in turn lead to activation of MAPK and AKT, respectively.…”