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Development Thrombopoetin signaling via JAK-STAT pathway


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Development Thrombopoetin signaling via JAK-STAT pathway

Thrombopoietin signaling pathway

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 ) kinase. JAK2 carries out tyrosine phosphorylationof multiple cellular proteins, including c-MPL itself, which results in a seriesof signaling events, such as activation of SHC transforming protein (Shc)/ v-Ha-rasHarvey rat sarcoma viral oncogene homolog (H-Ras)/Mitogen-activated protein kinase (MAPK)and Phosphoinositide-3-kinase (PI3K)/V-akt murine thymoma viral oncogene homolog 1(AKT(PKB)) cascades [3].

Another direction of Thrombopoietin signaling is carried out by signaltransducers and activators of transcription ( STAT ), recruited by phosphorylatedc-MPL and also subjected to phosphorylation by JAK2. STAT1,STAT3 and STAT5 phosphorylation was demonstrated in response toc-MPL activation. [2] Phosporylated STAT s homo- andheterodimerize, translocate to the nucleus and stimulate transcription of genes criticalfor cell proliferation and survival, such as Cyclin D1, Cyclin-dependent kinaseinhibitor 1A ( p21 ), Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ) andBCL2-like 1 ( Bcl-XL ) [3], [1]. Some other target genesactivated by STAT s, particularly in response to Thrombopoietin action, areSerpin peptidase inhibitor clade A member 3 ( SERPINA3 (ACT) ) [4],Transporter 1 ATP-binding cassette sub-family B ( TAP1 ) [5],C-reactive protein ( CRP ) [6] and Oncostatin M [7].

There are several ways Thrombopoietin signal can be turned off. One of them ismediated by Protein tyrosine phosphatase, non-receptor type 6 and 11 ( SHP-1 andSHP-2 ) coupled with Signal-regulatory protein alpha ( SHPS-1 ). Theydephosphorylate JAK2 leading to loss of its activity [8], [3]. Other way includes action of Suppressor of cytokine signaling ( SOCS )family of proteins, which create autoregulatory loop with STATS s: beingtransactivated by STATs, they inhibit JAK2 (in case of SOCS1 andSOCS3 ) or c-MPL (in case of Cytokine inducible SH2-containing protein (CISH )) [3]. Moreover, STAT1 and STAT3 could beinactivated by specific inhibitors Protein inhibitor of activated STAT 1 ( PIAS1 )[9] and Protein inhibitor of activated STAT 3 ( PIAS3 ) [10] respectively.