Thrombopoietin: a pan-hematopoietic cytokine

Geddis, Amy E.; Linden, Hannah M.; Kaushansky, Kenneth

doi:10.1016/s1359-6101(01)00030-2

Cited by 82 publications

(68 citation statements)

References 177 publications

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“…In contrast, related growth factors, EPO, granulocyte colony-stimulating factor, and growth hormones have all been shown to act in an antiapoptotic fashion on neurons (4,21,23,25,30,37). Similarly, TPO has antiapoptotic effects in the hematopoietic system (1)(2)(3)34). To the best of our knowledge, the previously uncharacterized proapoptotic function of TPO in the nervous system has not yet been described for any other cell type.…”

Section: Discussionmentioning

confidence: 95%

“…Likewise, they bind to receptors, erythropoietin receptor (EPOR) and thrombopoietin receptor (TPOR), respectively, that belong to the same cytokine receptor superfamily (1)(2)(3)(8)(9)(10). Previous studies reported a neurotrophin-like motif in the N-terminal receptor binding region of the TPO molecule, with conflicting data about the presence of TPO in the brain (5,6,(11)(12)(13).…”

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confidence: 99%

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A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

Ehrenreich

Hasselblatt

Knerlich

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1͞2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired targetderived neurotrophic support.astrocytes ͉ erythropoietin ͉ neurons ͉ differentiation ͉ development I n the hematopoietic system, survival, proliferation, and differentiation of cells are regulated by a plethora of growth factors (1-4). The effect of erythropoietin (EPO) on the generation of red blood cells is well known. The hematopoietic growth factor thrombopoietin (TPO) stimulates megakaryopoiesis and thrombocyte formation (1-3, 5, 6). During hematopoiesis, EPO and TPO can interact in a synergistic and an antagonistic fashion (1-3, 7).EPO and TPO exhibit significant homology in their receptorbinding domain (20% identity and 25% similarity). Likewise, they bind to receptors, erythropoietin receptor (EPOR) and thrombopoietin receptor (TPOR), respectively, that belong to the same cytokine receptor superfamily (1)(2)(3)(8)(9)(10). Previous studies reported a neurotrophin-like motif in the N-terminal receptor binding region of the TPO molecule, with conflicting data about the presence of TPO in the brain (5,6,(11)(12)(13).For EPO, it is well established that the gene is expressed in the embryonic CNS. EPO has a marked effect as a survival factor for neurons and their progenitors (14, 15), presumably to overcome phases of physiological hypoxia (16, 17). The widespread but rather ''unspecific'' neuroprotective potential of EPO is regained in the adult CNS upon distress or injury. This finding has been confirmed in rodent models of cerebral ischemia (18-23), brain trauma (18), and neurodegenerative disease (18), as well as in a clinical study with stroke patients (24).Here we show that TPO plays a previously unrecognized proapoptotic role in the brain. Materials and MethodsAll experiments were approved by and conducted in accordance with the regulations of the local Animal Care and Use Committee. For detailed information on all methods see Supporting Materials and Methods, which is published as supporting information on the PNAS web site.Cell Culture. Primary hippocampal neuronal cultures were prepared from newborn Wistar-Imamichi rats, cultured under serum-free conditions (25, 26), and used for experiments after five days (purity: Ͼ95% neurons). Neuronal cell number and viability was assessed by try...

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

Ehrenreich

Hasselblatt

Knerlich

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…DNA fragment coding the extracellular domain of murine IL-25R, a gift from Dr. J. D. Shaughnessy (University of Arkansas for Medical Sciences, Little Rock, AR) (12) was fused to the fragment coding C-terminal 187 aa of MPL, a receptor for thrombopoietin (22), and cloned into expression vector pCDNA3 (pCDNA3 IL-25R-MPL). Expression vectors for WT TRAF2, dominant negative (DN) TRAF2, Flag-tagged WT TRAF6, and Flag-tagged DN TRAF6 were previously described (23).…”

Section: Plasmidsmentioning

confidence: 99%

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

Maezawa

Nakajima

Suzuki

et al. 2006

The Journal of Immunology

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IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-κB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-κB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-κB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-β, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-κB activation and gene expression.

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“…Thrombopoietin (TPO) is an essential hematopoietic cytokine that regulates megakaryocytopoiesis via the activation of its cognate receptor, Mpl, expressed on hematopoietic stem cells and megakaryocytic cells (for reviews, see Drachman, 1 Geddis et al, 2 and Kaushansky 3 ). Like other cytokine receptors, Mpl does not contain a kinase domain but, rather, activates members of the receptor-associated Janus kinase (JAK) family on TPO stimulation.…”

Section: Introductionmentioning

confidence: 99%

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

Lannutti

Drachman

2004

Blood

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In this study we demonstrate that thrombopoietin (TPO)-stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, PP2), we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyndeficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2) , IntroductionThrombopoietin (TPO) is an essential hematopoietic cytokine that regulates megakaryocytopoiesis via the activation of its cognate receptor, Mpl, expressed on hematopoietic stem cells and megakaryocytic cells (for reviews, see Drachman, 1 Geddis et al, 2 and Kaushansky 3 ). Like other cytokine receptors, Mpl does not contain a kinase domain but, rather, activates members of the receptor-associated Janus kinase (JAK) family on TPO stimulation. Accumulated evidence shows that JAK2 is critical for megakaryocyte (MK) development and that once activated, JAK2 phosphorylates the fourth tyrosine of the Mpl cytoplasmic domain (Y112) and associated signaling molecules, resulting in the activation of the Jak/signal transducer and activator of transcription (STAT) and Ras/Raf/MAPK pathways. [4][5][6][7][8] The JAK/STAT pathway is essential for TPO-stimulated proliferation, whereas the activation of mitogenactivated protein kinase (MAPK) promotes differentiation, especially during sustained activation. 9,10 TPO activation of both the JAK/STAT and MAPK pathways has been well established in both cell lines and primary cells. [11][12][13] However, the complexity of signaling networks suggests that other cellular kinases, such as the Src family of tyrosine kinases, may be activated following TPO/Mpl interaction.The Src kinase family consists of 8 members (Src, Yes, Fgr, Fyn, Lck, Lyn, Blk, and Hck) that regulate a variety of cellular functions including proliferation, differentiation, and migration, depending on cellular milieu. 14,15 Comparison of all 8 Src family kinases (SFKs) reveals a modular organization that determines subcellular organization, protein-protein interactions, and function. 16 The amino-terminal myristoylation and palmitoylation sequences direct SFKs to the inner surface of the cell membrane. The Src homology 3 (SH3) domain directs association with polyproline motifs on interacting signaling molecules, whereas the SH2 domain binds phosphotyrosine residues in a sequence-specific manner. The kinase domain contains an adenosine triphosphate (ATP)-binding site and a catalytic tyrosine re...

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Thrombopoietin: a pan-hematopoietic cytokine

Cited by 82 publications

References 177 publications

A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

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