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Development EPO-induced MAPK pathway

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Development EPO-induced MAPK pathway

EPO-induced MAPK pathway

Erythropoiesis is the main pathway of pluripotent hematopoietic stem cell developmentinto mature end stage cells. Erythropoietin ( Epo ) is a major 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],composed of two identical subunits. Upon ligand binding, the two subunits dimerize andJanus kinase JAK2 is recruited to the receptor complex resulting in thephosphorylation of several tyrosine residues on Epo receptor [5],[6], [7]. Activated JAK2 initiates Epo-induced JAK/STATsignaling [8].

Once phosphorylated Epo receptor recruits and activates a number of downstreamadaptors and effectors including MAPK (mitogen-activated protein kinase) cascade and JNK(Jun N-terminal Kinases) pathway [9].

Activated Epo receptor complex recruits adapter proteins Shc andGRB2, leading to activation of the classical Shc/ GRB2/ SOS/ Ras/ c-Raf-1/ MEK/ ERK cascade, which is involved incell proliferation [10].

Epo receptor, adapter protein Shc and phosphatidyl-inositolpolyphosphate 5-phosphatase SHIP form a complex in hematopoietic cells, andSHIP is involved in Epo-induced signaling as an adapter protein [11],[12].

Transmembrane receptor c-Kit is the receptor for mast cell growth factor (MGF ). c-Kit can interact with and phosphorylate the Epo receptor,resulting in enhanced erythroid cell differentiation and proliferation [10].

Epo receptor transduces signals by activating physically associated tyrosinekinases, mainly JAK2 and Lyn, and, thereby, inducing tyrosinephosphorylation of various substrates including the Epo receptor itself, adapterproteins CrkL and c-Cbl and tyrosine kinases Syk and Btk[13], [14], [15], [16]. CrkLassociates with Shc and c-Cbl in hematopoietic cells. CrkL isconstitutively associated with guanine nucleotide exchange factor C3G, that alsobinds Shc [17]. C3G modulates activity of the Ras familyGTPases, such as RAP-1A [18], which, in turn, inhibits c-Raf-1kinase signaling [19].

Phospholipase C ( PLC-gamma 1 ) is an adapter protein which is rapidly tyrosinephosphorylated (e.g. by Btk kinase) upon Epo stimulation. PLC-gamma1 interacts with GRB2 and SOS2, leading to activation of the ERKpathway [20].

Phosphorylated by Btk, Syk and Lyn, phospholipasePLC-gamma also triggers activation of several isoforms of protein kinase C,including PKC-alpha and PKC-epsilon, via diacylglycerol ( DAG )production and Ca(2+) influx [21], [22], [23], [24]. PKC isoforms, in turn, can phosphorylate c-Raf-1kinase, leading to MAPK cascade activation [25], [26].

In primary human erythroid progenitor cells, phosphatidylinositol-3 kinase,PI3K-gamma, is activated by low concentration of Epo. MEK1 andERK1/2 kinases, through a Raf-independent signaling pathway, are signal mediatorsof PI3K-gamma [25]. PI3K-gamma is activated, probably, byH-Ras [27] and/or G-proteins beta/gamma [28].

Epo stimulation activates guanine nucleotide exchange factor VAV-1[29]. VAV-1 is involved in proliferative signals in hematopoietic cellsvia activation of small GTPase Rac1 that stimulates both JNK1-3 kinasesand MEK ( MEK1 and MEK2 )/ ERK1/2 cascade [30], [31], [32], [33], [26], [34].JNK1-3 and ERK1/2 kinases, in turn, phosphorylate transcription factorsElk-1, c-Jun and c-Fos that are crucial for cell proliferation[35], [36], [37].