gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with stat5gab2促进造血干细胞的维护和自我更新和stat5增效剂.pdfVIP

Gab2 Promotes Hematopoietic Stem Cell Maintenance and Self-Renewal Synergistically with STAT5 Geqiang Li1,2, Zhengqi Wang1,2, Kristy L. Miskimen1,2, Yi Zhang1¤a, William Tse1,2¤b, Kevin D. Bunting1,2,3* 1 Division of Hematology-Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America, 2 Center for Stem Cell and Regenerative Medicine, Cleveland, Ohio, United States of America, 3 Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America Abstract Background: Grb2-associated binding (Gab) adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol–3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs). Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5), a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner. Methodology/Principal Findings: To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit+ Lin2Sca-1+ (KLS) cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5