Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.

Silvennoinen, Olli; Witthuhn, Bruce A.; Quelle, Frederick W.; Cleveland, John L.; Yi, Taolin; Ihle, James N.

doi:10.1073/pnas.90.18.8429

Cited by 484 publications

(263 citation statements)

References 28 publications

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“…Several studies indicate that the C-terminal tyrosine kinase domain of JAK-2 contains the characteristic autophosphorylation site of tyrosine kinases [32][33][34]. Given that tyrosine phosphorylation of JAK-2 increases its catalytic activity [32][33][34], we examined whether insulin activates JAK-2 kinase directly.…”

Section: Insulin Stimulates Jak-2 Kinase Activitymentioning

confidence: 99%

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Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

Begum

Ragolia

1999

Biochemical Journal

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Our recent studies indicate that insulin rapidly inactivates serine/threonine protein phosphatase-2A (PP-2A) by increasing tyrosine phosphorylation on the catalytic subunit. The exact mechanism of PP-2A inactivation by insulin in vivo is unclear. The Janus kinase (JAK) family of non-receptor protein tyrosine kinases constitute a novel type of signal-transduction pathway which is activated in response to a wide variety of polypeptide ligands, including insulin. In this study we investigated the potential role of JAK-2 in insulin-mediated tyrosine phosphorylation and inactivation of PP-2A using the rat skeletal muscle cell line L6. Co-immunoprecipitation studies revealed that PP-2A is associated with JAK-2 in the basal state. Insulin treatment did not alter JAK-2 association with PP-2A, but did increase JAK-2-mediated tyrosine phosphorylation of the PP-2A catalytic subunit and therefore inhibited PP-2A enzymic activity. Furthermore, PP-2A is associated with phosphoinositide 3-kinase (PI-3K) in the basal state and insulin treatment increases the catalytic activity of PI-3K bound to PP-2A. Pretreatment with AG-490, a specific JAK-2 inhibitor, and SpcAMP, a cAMP agonist, prevented the insulin-mediated increase in (i) JAK-2 kinase activity, (ii) PP-2A tyrosine phosphorylation, (iii) PP-2A inactivation and restored the enzyme activity to control levels, and (iv) PP-2A and JAK-2-associated PI-3K activity. These observations, together with the fact that insulin rapidly activates JAK-2 in L6 cells, and that this is accompanied by an increase in tyrosine phosphorylation of PP-2A in JAK-2 immunoprecipitates, suggest that insulin controls the activation status of PP-2A by tyrosine phosphorylation via JAK-2. PP-2A inactivation may result in an amplification of insulin-generated signals at the level of PI-3K.

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Section: Insulin Stimulates Jak-2 Kinase Activitymentioning

confidence: 99%

“…Given that tyrosine phosphorylation of JAK-2 increases its catalytic activity [32][33][34], we examined whether insulin activates JAK-2 kinase directly. In this experiment, JAK-2 was immunoprecipitated and the kinase activity was measured in itro using [γ-$#P]ATP.…”

Section: Insulin Stimulates Jak-2 Kinase Activitymentioning

confidence: 99%

Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

Begum

Ragolia

1999

Biochemical Journal

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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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“…5 phosphorylation, it rather inhibited the IL-3-induced tyrosine phosphorylation of STAT 5 as well as the following proliferation. These data suggest that K-252a inhibits JAK 2 5,34 or another STAT 5 phosphorylating kinase.…”

Section: Figurementioning

confidence: 79%

Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e

1998

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Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.

Cited by 484 publications

References 28 publications

Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

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

Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e

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