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Development EPO-induced Jak-STAT pathway

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Development EPO-induced Jak-STAT pathway

EPO-induced Jak-STAT pathway

Erythropoiesis is a major pathway by which a pluripotent hematopoietic stem cell givesrise to mature end stage cells. Erythropoietin ( EPO ) is a lineage-specifichematopoietic growth factor required for survival, proliferation and differentiation ofcommitted erythroid progenitor cells [1], [2], [3].

EPO exerts its effect by binding to the EPO receptor [4],which is composed of two identical subunits. Upon ligand binding, the two subunitsdimerize and Janus kinase JAK2 is recruited to the receptor complex resulting inthe phosphorylation of several tyrosine residues on the receptor. These phosphorylatedtyrosine residues form docking sites for several molecules, including the signaltransducer and activator of transcription (STAT) transcription factors. The STATmolecules are phosphorylated on a single tyrosine residue by JAK kinases, leading todimerization and subsequent translocation to the nucleus where they act as transcriptionfactors [5]. STAT5 factors ( STAT5A and STAT5B) are the mostprominent STAT proteins activated by EPO receptor [6], [7]. STAT3 and STAT1 are also, albeit to a lesser extent, activatedby EPO stimulation [8], [9], [10].

CrkL, an adapter protein that is activated by binding to the EPOreceptor, can directly associate with STAT5A and inhibit its DNA bindingactivity [11], [12]. Kinases c-Src and JAK2cooperatively tyrosine-phosphorylate STAT5 [13].

EPO -induced activation of STATs is mainly involved in cell survival viaup-regulation of the expression of antiapopototic factors, such as Bcl-XL,XIAP, Pim-1, Bcl-2 and transcription factor c-Myc [14], [10], [15], [16], [17].

Protein kinase Lyn directly associates with EPO receptor, bindsto JAK2, and phosphorylates EPO receptor and STAT5 attyrosine residues, thus playing a role in activation of JAK2/ STAT5signaling [18].

Calcium-binding protein Calmodulin physically interacts with EPOreceptor and enhances JAK2 -mediated signaling [19].

EPO also activates the canonical kinase cascade H-Ras - c-Raf-1 -MEK1/2 - ERK1/2 by recruiting Shc/ GRB2/ Sos complexto the EPO receptor [20].

Besides tyrosine phosphorylation of STAT3 by JAK2, leading to nucleartranslocation, STAT3 proteins can be serine-phosphorylated by MSK1 kinase,which is activated upon MEK1/2 - ERK1/2 signal transduction cascade. It wasdemonstrated that serine phosphorylation of STAT3 augments its transactivationalpotential in erythroid cells [21].

c-Fes tyrosine kinase is also involved in EPO -induced activation ofSTAT3 [9], [22].

Expression of suppressors of cytokine signaling proteins SOCS1 and SOCS3(, or CISH (Cytokine-inducible SH2-containing protein) negatively regulatesEPO-mediated Jak-STAT signaling [23], [24]. On the other hand,SOCS3 binds to the GTPase activating protein p120GAP that attenuatesH-Ras inhibition and activates MEK1/2 - ERK1/2 cascade to ensurecell survival and proliferation [25].

The adaptor protein APS is tyrosine phosphorylated by JAK2, followed byrecruitment of the adaptor protein c-Cbl into the EPO receptor/JAK2 complex, which inhibits the JAK-STAT pathway [26].

Protein tyrosine phosphatases SHP-1 and SHP-2 are recruited to theEPO receptor/ JAK2 complex and dephosphorylate JAK2, inhibitingJAK-STAT signaling [27], [28], [29]. SHP-1 iscritical in negative regulation of STAT5 activation. SHP-1 is recruited toEPO receptor/ JAK2 complex that results in the recruitment of Grb2and its associated protein SOCS1. SOCS1 is targeted to JAK2,leading to JAK2/ STAT5 signaling inactivation [30].