Thrombopoietin signaling pathway
Thrombopoietin is a hormone involved in biological effects on a broad spectrum of hematopoietic progenitor cells, including stem cells. It supports stem cell survival and expansion. It is primarily a key physiological regulator of steady-state megakaryocytopoiesis, the process of megakaryocyte production and maturation that ultimately results in formation of platelets. Thrombopoietin is a 332-amino acid glycoprotein constitutively produced by the liver, kidney, marrow stroma and other tissues. Circulating concentration is thought to be controlled by receptor mediated internalization and degradation of thrombopoietin by megakaryocytes and platelets , , .
Binding of Thrombopoietin with its receptor Myeloproliferative leukemia virus oncogene ( c-MPL ) leads to receptor homodimerization and subsequent activation of Janus kinase 2 ( JAK2 ) kinase. JAK2 carries out tyrosine phosphorylation of multiple cellular proteins, including c-MPL itself, which results in a series of signaling events, such as activation of SHC transforming protein (Shc)/ v-Ha-ras Harvey 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 .
Another direction of Thrombopoietin signaling is carried out by signal transducers and activators of transcription ( STAT ), recruited by phosphorylated c-MPL and also subjected to phosphorylation by JAK2. STAT1, STAT3 and STAT5 phosphorylation was demonstrated in response to c-MPL activation.  Phosporylated STAT s homo- and heterodimerize, translocate to the nucleus and stimulate transcription of genes critical for cell proliferation and survival, such as Cyclin D1, Cyclin-dependent kinase inhibitor 1A ( p21 ), Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ) and BCL2-like 1 ( Bcl-XL ) , . Some other target genes activated by STAT s, particularly in response to Thrombopoietin action, are Serpin peptidase inhibitor clade A member 3 ( SERPINA3 (ACT) ) , Transporter 1 ATP-binding cassette sub-family B ( TAP1 ) , C-reactive protein ( CRP )  and Oncostatin M .
There are several ways Thrombopoietin signal can be turned off. One of them is mediated by Protein tyrosine phosphatase, non-receptor type 6 and 11 ( SHP-1 and SHP-2 ) coupled with Signal-regulatory protein alpha ( SHPS-1 ). They dephosphorylate JAK2 leading to loss of its activity , . Other way includes action of Suppressor of cytokine signaling ( SOCS ) family of proteins, which create autoregulatory loop with STATS s: being transactivated by STATs, they inhibit JAK2 (in case of SOCS1 and SOCS3 ) or c-MPL (in case of Cytokine inducible SH2-containing protein ( CISH )) . Moreover, STAT1 and STAT3 could be inactivated by specific inhibitors Protein inhibitor of activated STAT 1 ( PIAS1 )  and Protein inhibitor of activated STAT 3 ( PIAS3 )  respectively.