Development - Thrombopoetin signaling via JAK-STAT pathway

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 [1], [2], [3].

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 [3].

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. [2] 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) [1], [3]. Some other target genes activated by STATs, particularly in response to Thrombopoietin action, are Serpin 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 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 [3], [8]. 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)) [3]. Moreover, STAT1 and STAT3 could be inactivated by specific inhibitors Protein inhibitor of activated STAT 1 (PIAS1) [9] and Protein inhibitor of activated STAT 3 (PIAS3) [10] respectively.

References:

1. Kaushansky K
   Thrombopoietin: a tool for understanding thrombopoiesis. Journal of thrombosis and haemostasis : JTH 2003 Jul;1(7):1587-92
2. Fishley B, Alexander WS
   Thrombopoietin signalling in physiology and disease. Growth factors (Chur, Switzerland) 2004 Sep;22(3):151-5
3. Geddis AE, Linden HM, Kaushansky K
   Thrombopoietin: a pan-hematopoietic cytokine. Cytokine & growth factor reviews 2002 Feb;13(1):61-73
4. Kordula T, Rydel RE, Brigham EF, Horn F, Heinrich PC, Travis J
   Oncostatin M and the interleukin-6 and soluble interleukin-6 receptor complex regulate alpha1-antichymotrypsin expression in human cortical astrocytes. The Journal of biological chemistry 1998 Feb 13;273(7):4112-8
5. Rouyez MC, Lestingi M, Charon M, Fichelson S, Buzyn A, Dusanter-Fourt I
   IFN regulatory factor-2 cooperates with STAT1 to regulate transporter associated with antigen processing-1 promoter activity. Journal of immunology (Baltimore, Md. : 1950) 2005 Apr 1;174(7):3948-58
6. Zhang D, Sun M, Samols D, Kushner I
   STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. The Journal of biological chemistry 1996 Apr 19;271(16):9503-9
7. Yoshimura A, Ichihara M, Kinjyo I, Moriyama M, Copeland NG, Gilbert DJ, Jenkins NA, Hara T, Miyajima A
   Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway. The EMBO journal 1996 Mar 1;15(5):1055-63
8. Carter-Su C, Rui L, Stofega MR
   SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Recent progress in hormone research 2000;55:293-311
9. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K
   Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences of the United States of America 1998 Sep 1;95(18):10626-31
10. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K
    Specific inhibition of Stat3 signal transduction by PIAS3. Science (New York, N.Y.) 1997 Dec 5;278(5344):1803-5