Development - Thrombopoietin-regulated cell processes

Thrombopoietin-regulated cell processes

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). Activated JAK2 carries out tyrosine phosphorylation of multiple cellular proteins, by inducing phosphorylation of Myeloproliferative leukemia virus oncogene (c-Mpl) itself and recruitment of signaling proteins to the receptor via their SH2 domains. One of such proteins is SHC transforming protein (Shc), which in turn gets phosphorylated and recruits phosphorylated Growth factor receptor-bound protein 2 (GRB2) and Son of sevenless homolog (SOS), thereby activating small GTPase Harvey rat sarcoma viral oncogene homolog (H-Ras). GRB2 can also be associated with Vav guanine nucleotide exchange factor (VAV), that are guanine nucleotide exchange factors for Ras-related C3 botulinum toxin substrate 1 (Rac1) [4]. Activation of H-Ras is followed by recruitment of V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and activation of Mitogen-activated protein kinase kinase (MEK) and Mitogen-activated protein kinase (Erk). Moreover, Thrombopoietin can activate Erk via Rap1, which activates v-raf murine sarcoma viral oncogene homolog B1 (B-Raf) [1]. Recently it has been shown that kinase FYN oncogene related to SRC, FGR, YES (Fyn) appears to be activated upon Thrombopoietin stimulation [3].

Activated Erk phosphorylates ribosomal protein S6 kinases 90kD (p90RSK). Both kinases are involved in activation of a number of transcription factors, such as cAMP responsive element binding protein 1 (CREB1), Activating transcription factor 1 (ATF-1), ELK1 member of ETS oncogene family (Elk-1), V-myc myelocytomatosis viral oncogene homolog (c-Myc), Jun oncogene (c-Jun), and V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos). All of them regulate transcription of cell cycle proteins, for example, Cyclin A2 and Cyclin D1, Cyclin-dependent kinase inhibitor 1B (p27KIP1) and Cyclin-dependent kinase inhibitor 1A (p21) [1], [2], [5], [6], [7], [8]. Besides, p90RSK phosphorylates and inactivates pro-apoptotic factor BCL2-associated agonist of cell death (BAD) [1], [9], [10].

Furthermore, Thrombopoietin stimulation leads to an activation of Phosphoinositide-3-kinase (PI3K) pathway [1]. JAK2 activates the regulatory subunit of PI3K (PI3K reg class 1A), for example, through Insulin receptor substrate 2 (IRS-2) phosphorylation [11]. De-repression of PI3K catalytic subunit facilitates its association with membrane-bound H-Ras. Activated catalytic subunit then phosphorylates membrane posphatidylinositol, and phosphorylated lipids create membrane targets for proteins containing PH domains, such as 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) and AKT(PKB) kinase activated by PDK [1].

AKT(PKB) has a number of downstream targets that are involved in cell survival and cell cycle. For example, AKT(PKB) inhibits transcription factors Forkhead box O3 and O1 (FOXO3A and FKHR), that modulate transcription of p27KIP1 and survival, respectively [1], [12], [13], [14]. Activation CREB1 by AKT(PKB) is shown [15]. AKT(PKB) can also modulate the activity of p27KIP1 and p21 by phosporylating them [16], [17], [18]. Moreover, AKT(PKB) phosphorylates and inhibits BAD [1]. AKT(PKB) also inhibits the activity of Glycogen synthase kinase 3 beta (GSK3 beta) and its phosphorylation of Cyclin D1 and c-Myc [1], [19].

In addition to its effects on AKT, PDK is also an activating kinase for Protein kinase C (PKC-zeta) and Ribosomal protein S6 kinase 70kDa (p70 S6 kinase1) [1]. Accumulation of atypical PKC-zeta in the nucleus during megakaryocytopoiesis [20] allows the assumption that this kinase is one of the main down-stream targets of PDK (PDPK1). Both PKC-zeta and p70 S6 kinase1 are involved in the process of translation initiation. Another type of PKC that is implicated in Thrombopoietin-induced processes is PKC-alpha [2].

References:

1. Geddis AE, Linden HM, Kaushansky K
   Thrombopoietin: a pan-hematopoietic cytokine. Cytokine & growth factor reviews 2002 Feb;13(1):61-73
2. Kaushansky K
   Thrombopoietin: a tool for understanding thrombopoiesis. Journal of thrombosis and haemostasis : JTH 2003 Jul;1(7):1587-92
3. Fishley B, Alexander WS
   Thrombopoietin signalling in physiology and disease. Growth factors (Chur, Switzerland) 2004 Sep;22(3):151-5
4. Bustelo XR
   Regulatory and signaling properties of the Vav family. Molecular and cellular biology 2000 Mar;20(5):1461-77
5. Beier F, LuValle P
   The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia. Molecular endocrinology (Baltimore, Md.) 2002 Sep;16(9):2163-73
6. Nakamura T, Okuyama S, Okamoto S, Nakajima T, Sekiya S, Oda K
   Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF-1 and ATF-2 in the complex at the ATF/CRE site. Experimental cell research 1995 Feb;216(2):422-30
7. Shaulian E, Karin M
   AP-1 in cell proliferation and survival. Oncogene 2001 Apr 30;20(19):2390-400
8. Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, Pestell RG, Greenberg ME
   Fos family members induce cell cycle entry by activating cyclin D1. Molecular and cellular biology 1998 Sep;18(9):5609-19
9. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ
   Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1995 Jan 27;80(2):285-91
10. Scheid MP, Schubert KM, Duronio V
    Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. The Journal of biological chemistry 1999 Oct 22;274(43):31108-13
11. Carter-Su C, Rui L, Herrington J
    Role of the tyrosine kinase JAK2 in signal transduction by growth hormone. Pediatric nephrology (Berlin, Germany) 2000 Jul;14(7):550-7
12. Tanaka M, Kirito K, Kashii Y, Uchida M, Watanabe T, Endo H, Endoh T, Sawada K, Ozawa K, Komatsu N
    Forkhead family transcription factor FKHRL1 is expressed in human megakaryocytes. Regulation of cell cycling as a downstream molecule of thrombopoietin signaling. The Journal of biological chemistry 2001 May 4;276(18):15082-9
13. Tang ED, Nu?ez G, Barr FG, Guan KL
    Negative regulation of the forkhead transcription factor FKHR by Akt. The Journal of biological chemistry 1999 Jun 11;274(24):16741-6
14. Daly C, Wong V, Burova E, Wei Y, Zabski S, Griffiths J, Lai KM, Lin HC, Ioffe E, Yancopoulos GD, Rudge JS
    Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes & development 2004 May 1;18(9):1060-71
15. Du K, Montminy M
    CREB is a regulatory target for the protein kinase Akt/PKB. The Journal of biological chemistry 1998 Dec 4;273(49):32377-9
16. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM
    PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature medicine 2002 Oct;8(10):1153-60
17. Li Y, Dowbenko D, Lasky LA
    AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. The Journal of biological chemistry 2002 Mar 29;277(13):11352-61
18. El-Deiry WS
    Akt takes centre stage in cell-cycle deregulation. Nature cell biology 2001 Mar;3(3):E71-3
19. Gregory MA, Qi Y, Hann SR
    Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. The Journal of biological chemistry 2003 Dec 19;278(51):51606-12
20. Marchisio M, Bertagnolo V, Celeghini C, Vitale M, Capitani S, Zauli G
    Selective modulation of specific protein kinase C (PKC) isoforms in primary human megakaryocytic vs. erythroid cells. The Anatomical record 1999 May 1;255(1):7-14