Resolving conflicting signals: cross inhibition of cytokine signaling pathways

CG Begley, NA Nicola - Blood, The Journal of the American …, 1999 - ashpublications.org
CG Begley, NA Nicola
Blood, The Journal of the American Society of Hematology, 1999ashpublications.org
THE GENERATION of hematopoietic cells requires the coordinated response to a plethora
of stimulatory and inhibitory signals that cells receive from their extracellular environment.
The ''positive''regulators are relatively well defined: the molecules that stimulate the
proliferation, differentiation, and survival of hematopoietic cells have been extensively
studied. These include the colony-stimulating factors (CSFs) and the majority of the
interleukins (ILs). Several of these molecules are available for clinical use, and much is …
THE GENERATION of hematopoietic cells requires the coordinated response to a plethora of stimulatory and inhibitory signals that cells receive from their extracellular environment. The ‘‘positive’’regulators are relatively well defined: the molecules that stimulate the proliferation, differentiation, and survival of hematopoietic cells have been extensively studied. These include the colony-stimulating factors (CSFs) and the majority of the interleukins (ILs). Several of these molecules are available for clinical use, and much is known about their structure, the consequences of their overproduction, and the biological effects that result from their complete absence. The multi-protein receptor complexes that are used by these molecules at the cell surface have been characterized to reveal a complicated interplay of shared receptor components and unique receptor elements. More recently the intracellular pathways that are triggered by growth factor/receptor interactions have begun to be dissected, revealing an interdigitating network of signaling molecules that is striking both in terms of its complexity, and in terms of the recurring themes that are revealed in otherwise apparently divergent experimental systems. 1 By comparison, the ‘‘negative’’regulators of hematopoiesis have been relatively neglected. However, it has been clear for a number of years that molecules like transforming growth factor-(TGF-) are potent negative regulators of hematopoiesis and function as important molecules in determining hematopoietic responses. The identification of the JAK/STAT signaling pathway provided an understanding of one mechanism by which stimulatory signals received at the cell surface are rapidly transmitted to the nucleus. The JAKs (or Janus kinases) are receptor-associated molecules that are phosphorylated on tyrosine in response to cytokine-receptor interactions. As a consequence, the STAT (for signal transducers and activators of transcription) molecules are recruited to the receptor and phosphorylated. 2, 3 This leads to their dimerization and translocation to the nucleus where they bind and activate transcription of target genes. The recruitment of particular JAK/STAT family members overlaps but differs for different cytokines. Thus, for example, IL-6 type cytokines use JAK1, JAK2, and the related molecule TYK2, and STAT1 and STAT3, 4, 5 although the critical molecules appear to be JAK1 and STAT3. 6, 7 In comparison, the IL-12 signaling pathway results in phosphorylation of JAK2 and TYK28, 9 and requires STAT4 for IL-12–generated responses. 10, 11 The mechanism by which ‘‘negative’’regulators exert their inhibitory action is less clear. One possible mechanism involves the recruitment of protein tyrosine phosphatases that can then serve to inactivate JAK proteins. One such is SHP-1, the defective function of which results in the hyperproliferation and accumulation of several hematopoietic cell lineages and in the development of autoimmune disease as evidenced by the motheaten mouse. 12 Specific targeting of this molecule to the erythropoietin receptor can inhibit ligand-stimulated tyrosine phosphorylation and result in dephosphorylation of JAK2. 13 The negative regulator TGF-has been reported to activate protein tyrosine phosphatases14 and this may be one mechanism by which it exerts its inhibitory effect on the JAK/STAT pathway. 15
Another family of signaling molecules that are potentially important mediators of inhibitory signals have recently been described. There appear to be at least 8 of these ‘‘SOCS’’proteins (for suppressors of cytokine signaling) including CIS, an early response gene, that encode SH2-domain containing proteins16-19 and …
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