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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2351-2359
HEMATOPOIESIS
Role of the docking protein Gab2 in  1-integrin
signaling pathway-mediated hematopoietic cell adhesion and
migration
Wen-Mei Yu,
Teresa S. Hawley,
Robert G. Hawley, and
Cheng-Kui Qu
From the Department of Hematopoiesis, Jerome H. Holland
Laboratory for the Biomedical Sciences, American Red Cross, Rockville,
MD, and Department of Anatomy and Cell Biology, George Washington
University School of Medicine and Health Sciences, Washington,
DC.
Gab2, a newly identified pleckstrin homology domain-containing
docking protein, is a major binding protein of SHP-2 tyrosine phosphatase in interleukin (IL)-3-stimulated hematopoietic cells. Its
signaling mechanism remains largely unknown. We report here an
important regulatory role for Gab2 in  1 integrin
signaling pathway that mediates hematopoietic cell adhesion and
migration. Cross-linking of the 1 integrin on Ba/F3
cells induced rapid tyrosine phosphorylation of Gab2 and its
association with Syk kinase, SHP-2 phosphatase, and the p85 subunit of
phosphatidylinositol (PI)-3 kinase. In addition, Gab2 was also
constitutively associated with SHP-1 phosphatase via its
C-terminal Src homology 2 domain. Overexpression of the pleckstrin
homology domain or a mutant Gab2 molecule lacking SHP-2 binding
sites resulted in significant reductions in Ba/F3 cell adhesion and
migration. Biochemical analyses revealed that enforced expression of
Gab2 mutant molecules dramatically reduced 1-integrin
ligation-triggered PI3 kinase activation, whereas Erk kinase activation
remained unaltered. Furthermore, transduction of primary hematopoietic
progenitor cells from viable motheaten mice with
these mutant Gab2 molecules also significantly ameliorated their
enhanced migration capacity associated with the
SHP1 gene mutation. Taken together, these results
suggest an important signaling role for Gab2 in regulating
hematopoietic cell adhesion and migration.
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