Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development Thrombopoietin-regulated cell processes


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Development Thrombopoietin-regulated cell processes

Thrombopoietin-regulated cell processes

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 ). Activated JAK2 carries out tyrosinephosphorylation of multiple cellular proteins, by inducing phosphorylation ofMyeloproliferative leukemia virus oncogene ( c-Mpl ) itself and recruitment ofsignaling proteins to the receptor via their SH2 domains. One of such proteins is SHCtransforming protein ( Shc ), which in turn gets phosphorylated and recruitsphosphorylated Growth factor receptor-bound protein 2 ( GRB2 ) and Son ofsevenless homolog (SOS ), thereby activating small GTPase Harvey rat sarcoma viraloncogene homolog ( H-Ras ). GRB2 can also be associated with Vav guaninenucleotide exchange factor ( VAV ), that are guanine nucleotide exchange factorsfor Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) [2],[4], [5], [6], [7]. Besides,p90RSK phosphorylates and inactivates pro-apoptotic factor BCL2-associated agonistof cell death ( BAD ) [8], [9].

Furthermore, Thrombopoietin stimulation leads to an activation ofPhosphoinositide-3-kinase ( PI3K ) pathway [10], [11], [12]. Activa tion CREB1 by AKT(PKB) is shown [13]. AKT(PKB) can also modulate the activity of p27KIP1 andp21 by phosporylating them [14], [15], [16].Moreover, AKT(PKB) phosphorylates and inhibits BAD [1], [17].

In addition to its effects on AKT, PDK is also an activating kinase forProtein kinase C ( PKC-zeta ) and Ribosomal protein S6 kinase 70kDa ( p70 S6kinase1 ) [1]. Accumulation of atypical PKC-zeta in the nucleusduring megakaryocytopoiesis [18] allows the assumption that this kinase isone of the main down-stream targets of PDK (PDPK1). Both PKC-zeta andp70 S6 kinase1  are involved in the process of translation initiation. Anothertype of PKC that is implicated in Thrombopoietin -induced processes isPKC-alpha [2].