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))
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
STAT3 and STAT5 phosphorylation
was demonstrated in response to c-MPL activation.  Phosporylated STATs 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 STATs, 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 STATSs: 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.
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