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Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
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RAS - superfamily
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Voltage-gated channel
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
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Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

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.