JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin

Witthuhn, Bruce A.; Quelle, Frederick W.; Silvennoinen, Olli; Yi, Taolin; Tang, Bo; Miura, Osamu; Ihle, James N.

doi:10.1016/0092-8674(93)90414-l

Cited by 1,144 publications

(640 citation statements)

References 39 publications

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“…3Aa and 3Ba). As it is generally accepted that tyrosine phosphorylation of JAKs is associated with the activation of kinase activity [13,23], TPO treatment increased in vitro kinase activity of Tyk2 and JAK2 in parallel with tyrosine phosphorylation of these kinases (data not shown).…”

Section: Tyrosine Phosphorylation Of Jak Family Kinases Tyk2 and Jakmentioning

confidence: 80%

See 1 more Smart Citation

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

1995

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We investigated in vitro effects of recombinant human thrombopoietin (TPO), or c-Mpl ligand, on human platelets. TPO induced rapid dose-dependent tyrosine phosphorylation of several proteins. We identified Janus tyrosine kinases, Tyk2 and JAK2, and a member of STAT (signal transducers and activators of transcription) family, STAT3, as the tyrosine-phosphorylated proteins in response to TPO. TPO by itself did not cause platelet aggregation and shape change, but augmented ADP-indnced aggregation in a dose-dependent manner. Acetyisalicylic acid inhibited the secondary aggregation enhanced by TPO, but not the TPO-induced potentiation of the primary aggregation. TPO modulates platelet activation possibly through protein-tyrosine phosphorylation.

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Section: Tyrosine Phosphorylation Of Jak Family Kinases Tyk2 and Jakmentioning

confidence: 80%

“…In some experiments, the membranes once probed were stripped of bound antibodies and reprobed with other antibodies. In vitro kinase activity of immunoprecipitated JAKs was determined as previously described [23].…”

Section: Lmmunoprecipitation Immunoblotting and In Vitro Kinase Assaysmentioning

confidence: 99%

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

1995

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“…JAK2/STAT5 play a key role in initiating EPO-R activation and subsequent recruitment of signaling modules to the receptor (Richmond et al, 2005;Witthuhn et al, 1993).…”

Section: Epo Preferentially Activates Stat3 In Bm-dcsmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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“…The corresponding receptors for these factors lack endogenous tyrosine kinase activity but mediate their responses by using JAK proteins for tyrosine phosphorylation of the activated receptor. [7][8][9] The phosphorylated receptors then stimulate intracellular signalling cascades by binding and activating cytoplasmic proteins. Many of these proteins share a common structural motif, the Src homology 2 (SH2) domain, that plays a role as docking site for other tyrosine phosphorylated proteins.…”

Section: Introductionmentioning

confidence: 99%

Unconventional rapid ERK1,2 activation is indispensable for proliferation of the growth factor-independent myeloid leukemic cell line KG1

Barge¹,

Dorrestijn

Falkenburg³

et al. 1998

Leukemia

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While normal hematopoietic progenitor cells are dependent on colony-stimulating factors for in vitro proliferation, myeloid leukemic cells are frequently factor-independent. In this study we investigated several signalling intermediates of the Ras-Erk1,2 pathway which may be involved in the development of growth factor independence. In the growth factor independent cell line KG1, an extremely short activation pattern of Erk1,2 with a maximum at 30 s was observed in response to FBS. In contrast, stimulation of the IL-3 receptor in AML193 cells resulted in a transient Erk activation peaking at 5 min and returning to base levels after 15 min. Although the Erk activation in KG1 cells is short-lived, using the MEK inhibitor PD98059, we demonstrated that Erk phosphorylation is essential for proliferation of these cell lines. We also detected major differences in Shc phosphorylation between factor-dependent and -independent cells. These data suggest that Erk activation is essential for proliferation of growth factor-dependent and -independent leukemic cells. The minimal Erk activation observed in KG1 cells in response to serum is sufficient for mitogenesis of these cells.

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JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin

Cited by 1,144 publications

References 39 publications

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Unconventional rapid ERK1,2 activation is indispensable for proliferation of the growth factor-independent myeloid leukemic cell line KG1

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