Gab1 mediates hepatocyte growth factor-stimulated mitogenicity and morphogenesis in multipotent myeloid cells.
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.
Felici
Angelina
A
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National, Institutes of Health, Bethesda, Maryland 20892-1501, USA.
Giubellino
Alessio
A
Bottaro
Donald P
DP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D050989:GATA2 Transcription Factor; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D051379:Mice; D008934:Mitogens; D009024:Morphogenesis; D039902:Multipotent Stem Cells / Q000502:physiology*; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D019859:Proto-Oncogene Proteins c-met; D011554:Pseudopodia
D048868:Adaptor Proteins, Signal Transducing; D050989:GATA2 Transcription Factor; C490897:Gab1 protein, mouse; C494712:Gata2 protein, mouse; D008934:Mitogens; D010750:Phosphoproteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse