Abnormal hematopoiesis in Gab2 mutant mice.
Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit(+)Lin(-)Sca-1(+) (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colony-forming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit(+)Lin(-) cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) signaling cascades. Associated with the early defects in cytokine response, competitive transplantation of Gab2(-/-) bone marrow cells resulted in defective long-term multilineage repopulation. Therefore, we demonstrate that Gab2 adapter function is intrinsically required for hematopoietic cell response to early-acting cytokines, resulting in defective hematopoiesis in Gab2-deficient mice.
Zhang
Yi
Y
Department of Medicine, Division of Hematology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-7284, USA.
Diaz-Flores
Ernesto
E
Li
Geqiang
G
Wang
Zhengqi
Z
Kang
Zizhen
Z
Haviernikova
Eleonora
E
Rowe
Sara
S
Qu
Cheng-Kui
CK
Tse
William
W
Shannon
Kevin M
KM
Bunting
Kevin D
KD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C490894:Gab2 protein, mouse; D010750:Phosphoproteins