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 , , .
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) . 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) . Recently it
has been shown that kinase FYN oncogene related to SRC, FGR, YES
(Fyn) appears to be activated upon
Thrombopoietin stimulation .
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) , , , , , . Besides,
p90RSK phosphorylates and inactivates pro-apoptotic factor
BCL2-associated agonist of cell death (BAD) , , .
Furthermore, Thrombopoietin stimulation leads to an
activation of Phosphoinositide-3-kinase (PI3K) pathway
. JAK2 activates the regulatory subunit of
PI3K (PI3K reg class 1A), for example, through Insulin
receptor substrate 2 (IRS-2) phosphorylation . 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
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
, , , . Activation
CREB1 by AKT(PKB) is shown
. AKT(PKB) can also modulate the activity of
p27KIP1 and p21 by
phosporylating them , , . Moreover,
AKT(PKB) phosphorylates and inhibits
BAD . AKT(PKB)
also inhibits the activity of Glycogen synthase kinase 3 beta (GSK3
beta) and its phosphorylation of
Cyclin D1 and c-Myc , .
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) . Accumulation of atypical
PKC-zeta in the nucleus during megakaryocytopoiesis  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
- Geddis AE, Linden HM, Kaushansky K
Thrombopoietin: a pan-hematopoietic cytokine.
Cytokine & growth factor reviews 2002 Feb;13(1):61-73
- Kaushansky K
Thrombopoietin: a tool for understanding thrombopoiesis.
Journal of thrombosis and haemostasis : JTH 2003 Jul;1(7):1587-92
- Fishley B, Alexander WS
Thrombopoietin signalling in physiology and disease.
Growth factors (Chur, Switzerland) 2004 Sep;22(3):151-5
- Bustelo XR
Regulatory and signaling properties of the Vav family.
Molecular and cellular biology 2000 Mar;20(5):1461-77
- 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
- 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
- Shaulian E, Karin M
AP-1 in cell proliferation and survival.
Oncogene 2001 Apr 30;20(19):2390-400
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- El-Deiry WS
Akt takes centre stage in cell-cycle deregulation.
Nature cell biology 2001 Mar;3(3):E71-3
- 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
- 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