Development Thrombopoietin-regulated cell processes
Thrombopoietin-regulated cell processes
Thrombopoietin is a hormone involved in biological effects on a broad spectrumof hematopoietic progenitor cells, including stem cells. It supports stem cell survivaland expansion. It is primarily a key physiological regulator of steady-statemegakaryocytopoiesis, the process of megakaryocyte production and maturation thatultimately results in formation of platelets. Thrombopoietin is a 332-amino acidglycoprotein constitutively produced by the liver, kidney, marrow stroma and othertissues. Circulating concentration is thought to be controlled by receptor mediatedinternalization and degradation of Thrombopoietin by megakaryocytes and platelets [1], [2], [3].
Binding of Thrombopoietin with its receptor Myeloproliferative leukemia virusoncogene (c-Mpl ) leads to receptor homodimerization and subsequent activation ofJanus kinase 2 ( JAK2 ). Activated JAK2 carries out tyrosinephosphorylation of multiple cellular proteins, by inducing phosphorylation ofMyeloproliferative leukemia virus oncogene ( c-Mpl ) itself and recruitment ofsignaling proteins to the receptor via their SH2 domains. One of such proteins is SHCtransforming protein ( Shc ), which in turn gets phosphorylated and recruitsphosphorylated Growth factor receptor-bound protein 2 ( GRB2 ) and Son ofsevenless homolog (SOS ), thereby activating small GTPase Harvey rat sarcoma viraloncogene homolog ( H-Ras ). GRB2 can also be associated with Vav guaninenucleotide exchange factor ( VAV ), that are guanine nucleotide exchange factorsfor Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) [2],[4], [5], [6], [7]. Besides,p90RSK phosphorylates and inactivates pro-apoptotic factor BCL2-associated agonistof cell death ( BAD ) [8], [9].
Furthermore, Thrombopoietin stimulation leads to an activation ofPhosphoinositide-3-kinase ( PI3K ) pathway [10], [11], [12]. Activa tion CREB1 by AKT(PKB) is shown [13]. AKT(PKB) can also modulate the activity of p27KIP1 andp21 by phosporylating them [14], [15], [16].Moreover, AKT(PKB) phosphorylates and inhibits BAD [1], [17].
In addition to its effects on AKT, PDK is also an activating kinase forProtein kinase C ( PKC-zeta ) and Ribosomal protein S6 kinase 70kDa ( p70 S6kinase1 ) [1]. Accumulation of atypical PKC-zeta in the nucleusduring megakaryocytopoiesis [18] allows the assumption that this kinase isone of the main down-stream targets of PDK (PDPK1). Both PKC-zeta andp70 S6 kinase1 are involved in the process of translation initiation. Anothertype of PKC that is implicated in Thrombopoietin -induced processes isPKC-alpha [2].
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