Grb2 regulates the proliferation of hematopoietic stem and progenitors cells.

Although Hematopoietic Stem and Progenitor Cell (HSPC) proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Our study showed that Growth factor receptor-bound protein 2 (Grb2) mRNAs are preferentially expressed in HSC compared to progenitors and differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a rapid decline of erythroid and myeloid progenitors and a progressive decline of HSC numbers in steady state conditions. We showed that when transplanted, Grb2 deleted bone marrow cells could not reconstitute irradiated recipients. Strinkingly, Grb2 deletion did not modify HSPC quiescence, but impaired LT-HSC and progenitors ability to respond a proliferative signal induced by 5FU in vivo and by various cytokines in vitro. We showed finally that Grb2 links IL3 signaling to the ERK/MAPK proliferative pathway and that both SH2 and SH3 domains of Grb2 are crucial for IL3 signaling in progenitor cells. Our findings position Grb2 as a key adaptor that integrates various cytokines response in cycling HSPC.