Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation.

Damen, Jacqueline E.; Wakao, Hiroshi; Miyajima, Atsushi; Krošl, Jana; Humphries, R. Keith; Cutler, Robert L.; Krystal, Gerald

doi:10.1002/j.1460-2075.1995.tb00243.x

Cited by 275 publications

(221 citation statements)

References 57 publications

(65 reference statements)

Supporting

Mentioning

205

Contrasting

Order By: Relevance

“…These and other studies implicate murine Epo receptor tyrosine residues Tyr 343 and Tyr 401 in Stat5 activation Damen et al, 1995;Quelle et al, 1996;Klingmuller et al, 1996). Although the myeloid leukemia cell lines used in these studies exhibit great variability in their responses to Epo-mediated Stat5 activation, cell lines that respond with erythroid di erentiation (e.g., ELM-I-1; SKT6) exhibit characteristics that more closely resemble committed erythroid progenitors.…”

Section: Epo Receptormentioning

confidence: 83%

Control of myeloid differentiation and survival by Stats

et al. 2000

View full text Add to dashboard Cite

Hematopoiesis involves a complex array of growth factors that regulate the survival and proliferation of immature progenitors, in¯uence di erentiation commitment, and modulate end-stage cell functions. This minireview is focused on the role of Stat activation in the development of myeloid cells in response to hematopoietic cytokines. Much of the evidence implicating Stats in these cellular processes comes from studies of mutant cytokine receptors selectively uncoupled from Stat activation, dominant-inhibitory Stat mutants, and mice with targeted disruptions of Stat genes. Together these approaches provide strong evidence that Stat activation, particularly of Stat3 and Stat5, plays an important role in myeloid di erentiation and survival. Oncogene (2000) 19, 2612 ± 2618.Keywords: stat; cytokine; di erentiation; survival; tyrosine kinase Mutant cytokine receptors lacking Stat recruitment sites fail to induce di erentiation gp130-based receptor system IL-6 and the related cytokines LIF, CNTF, OSM, IL-11 and CT-1 share structural features and a ect an overlapping set of target cells . The receptors for the IL-6 family of cytokines share a signal transducing subunit known as gp130, which provides a link to multiple signaling pathways via a tyrosine phosphorylation-dependent mechanism. This familiar signaling paradigm, shared by all of the cytokine receptor systems discussed here, is initiated by liganddependent receptor oligomerization, activation of receptor-associated tyrosine kinases, and phosphorylation of speci®c tyrosine residues within the receptor. A subset of these receptor phosphotyrosines recruit cytoplasmic Stats through their SH2 domains. The Stats are then phosphorylated by receptor-associated kinases, inducing dimerization, nuclear translocation, and transcriptional activation at speci®c promoter elements. As described in more detail below, regions of gp130 required for myeloid di erentiation are often required for Stat activation.The cytoplasmic region of gp130 responsible for Stat3 activation is also required for di erentiation signaling in the murine leukemia cell line, M1 . Both IL-6 and LIF induce growth arrest and macrophage di erentiation in this cell line. To avoid the complication of signaling from endogenous gp130, chimeric receptors were constructed in which the cytoplasmic region of gp130 was fused to the extracellular ligand-binding domain of growth hormone. The resulting chimeric receptor generated growth hormone-dependent signals for growth arrest and morphological changes indistinguishable from those of IL-6. Successive C-terminal truncations of the chimeric receptor identi®ed the distal 133 residues of gp130 as critical for the generation of signals for growth arrest, macrophage di erentiation, and Stat3 activation. Phosphorylation of Tyr 126 in this region of gp130 forms a binding site for the Stat3 SH2 domain (Y P XXQ motif) (Stahl et al., 1995). Mutagenesis of this site completely blocked di erentiation signaling and Stat3 activation from the truncated receptor. However, mutagenes...

show abstract

Section: Epo Receptormentioning

confidence: 83%

Control of myeloid differentiation and survival by Stats

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Several studies suggest that the EPO neuroprotective signaling pathways have some similarities to the pathways in erythropoiesis, including activations of Janus-tyrosine kinase 2 (Jak2) (Bittorf et al, 1997;Kawakami et al, 2001), signal transducers and activators of transcription (STATs) (Bittorf et al, 2000;Damen et al, 1995) and of nuclear factor kappaB (NFkB) (Figueroa et al, 2002;Matsushita et al, 2003). When the EPO molecule binds to the EPOR, a dimerization of the receptor occurs with subsequent autophosphorylation of Jak2 and receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

View full text Add to dashboard Cite

In addition to its well-known hematopoietic effects, erythropoietin (EPO) also has neuroprotective properties. However, hematopoietic side effects are unwanted for neuroprotection, underlining the need for EPO-like compounds with selective neuroprotective actions. One such compound, devoid of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate (NMDA) excitotoxicity. Hippocampal slice cultures were pretreated for 24 h with 100 IU/ml EPO (= 26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49 ± 3 or 35 ± 8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33 ± 5 and 15 ± 8%, respectively, in the OGD and NMDA exposed cultures. To elucidate a possible mechanism involved in EPO and CEPO neuroprotection against OGD, the integrity of α-II-spectrin cytoskeletal protein was studied. Both EPO and CEPO significantly reduced formation of spectrin cleavage products in the OGD model. We conclude that CEPO is at least as efficient neuroprotectant as EPO when excitotoxicity is modeled in mouse hippocampal slice cultures.

show abstract

“…Although a variety of studies attempted to de®ne the role of STAT5 in cell growth and di erentiation, its requirement for such processes is still a subject of dispute. Some data describe an implication of STAT5 in the control of proliferation (Damen et al, 1995;Friedmann et al, 1996;Mellitzer et al, 1996), whereas others show that receptor mutants lacking the ability to activate STAT5 are still able to transduce mitogenic signals (Quelle et al, 1996;Fujii et al, 1995). Moreover, while a dominant negative STAT5 protein was found to inhibit IL-3 driven DNA synthesis in Ba/F3 cells (Mui et al, 1996), the expression of another dominant negative STAT5 had no e ect on IL3-induced proliferation in myeloid cells .…”

Section: Discussionmentioning

confidence: 99%

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

et al. 1998

View full text Add to dashboard Cite

Overexpression of the mutationally activated Xmrk receptor initiates the formation of hereditary malignant melanoma in the ®sh Xiphophorus. In addition to transcriptional overexpression a cell-type speci®c signal transduction is essential for Xmrk mediated tumor formation. To elucidate the consequence of Xmrk signalling and to identify target proteins that characterize the tumor phenotype, we analysed proteins that are strongly tyrosine phosphorylated in the ®sh melanoma cell line PSM. One of the most prominent phosphotyrosine proteins was found to be the signal transducer and activator of transcription STAT5. In a heterologous cell system (murine pro B-cells), activation of the Xmrk kinase in a chimeric receptor induced tyrosine phosphorylation, nuclear translocation and DNA binding of STAT5. Following receptor stimulation, expression of the STAT5 speci®c target genes cis, osm and pim-1 was induced. In Xiphophorus PSM cells STAT5 was found to be preferentially localized in the nucleus, but treatment with tyrphostin AG555, a speci®c Xmrk kinase-inhibitor, blocked nuclear localization. In these cells as well as in Xiphophorus melanoma expression of pim-1 and constitutive DNA-binding activity of STAT5 was detectable. This constitutive activity was higher in malignant than in benign melanomas, indicating that STAT5 activation is correlated with the malignancy of these tumors.

show abstract

Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation.

Cited by 275 publications

References 57 publications

Control of myeloid differentiation and survival by Stats

Control of myeloid differentiation and survival by Stats

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

Contact Info

Product

Resources

About