Control of myeloid differentiation and survival by Stats

Abstract

Hematopoiesis involves a complex array of growth factors that regulate the survival and proliferation of immature progenitors, in¯uence di erentiation commitment, and modulate end-stage cell functions. This minireview is focused on the role of Stat activation in the development of myeloid cells in response to hematopoietic cytokines. Much of the evidence implicating Stats in these cellular processes comes from studies of mutant cytokine receptors selectively uncoupled from Stat activation, dominant-inhibitory Stat mutants, and mice with targeted disruptions of Stat genes. Together these approaches provide strong evidence that Stat activation, particularly of Stat3 and Stat5, plays an important role in myeloid di erentiation and survival. Oncogene (2000) 19, 2612 ± 2618.Keywords: stat; cytokine; di erentiation; survival; tyrosine kinase Mutant cytokine receptors lacking Stat recruitment sites fail to induce di erentiation gp130-based receptor system IL-6 and the related cytokines LIF, CNTF, OSM, IL-11 and CT-1 share structural features and a ect an overlapping set of target cells . The receptors for the IL-6 family of cytokines share a signal transducing subunit known as gp130, which provides a link to multiple signaling pathways via a tyrosine phosphorylation-dependent mechanism. This familiar signaling paradigm, shared by all of the cytokine receptor systems discussed here, is initiated by liganddependent receptor oligomerization, activation of receptor-associated tyrosine kinases, and phosphorylation of speci®c tyrosine residues within the receptor. A subset of these receptor phosphotyrosines recruit cytoplasmic Stats through their SH2 domains. The Stats are then phosphorylated by receptor-associated kinases, inducing dimerization, nuclear translocation, and transcriptional activation at speci®c promoter elements. As described in more detail below, regions of gp130 required for myeloid di erentiation are often required for Stat activation.The cytoplasmic region of gp130 responsible for Stat3 activation is also required for di erentiation signaling in the murine leukemia cell line, M1 . Both IL-6 and LIF induce growth arrest and macrophage di erentiation in this cell line. To avoid the complication of signaling from endogenous gp130, chimeric receptors were constructed in which the cytoplasmic region of gp130 was fused to the extracellular ligand-binding domain of growth hormone. The resulting chimeric receptor generated growth hormone-dependent signals for growth arrest and morphological changes indistinguishable from those of IL-6. Successive C-terminal truncations of the chimeric receptor identi®ed the distal 133 residues of gp130 as critical for the generation of signals for growth arrest, macrophage di erentiation, and Stat3 activation. Phosphorylation of Tyr 126 in this region of gp130 forms a binding site for the Stat3 SH2 domain (Y P XXQ motif) (Stahl et al., 1995). Mutagenesis of this site completely blocked di erentiation signaling and Stat3 activation from the truncated receptor. However, mutagenes...

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