Janus Kinases Affect Thrombopoietin Receptor Cell Surface Localization and Stability

Royer, Yohan; Staerk, Judith; Costuleanu, Marcel; Courtoy, Pierre J.; Constantinescu, Stefan N.

doi:10.1074/jbc.m501376200

Cited by 157 publications

(205 citation statements)

References 62 publications

(77 reference statements)

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“…Such down-modulation is not seen for EpoR. TpoR is a long-lived receptor at the cell surface 47 and recycles, 97 which is not the case for EpoR. Further experiments are necessary to follow up on the original observation of TpoR down-modulation in MPNs, which may be due to traffic alterations, excessive internalization and degradation or decreased protein synthesis.…”

Section: Tpor and Mpnsmentioning

confidence: 99%

Section: Tpor and Mpnsmentioning

confidence: 99%

“…47 However, JAK2 is much more effective than Tyk2 in transmitting the signals of the receptor. 47,64 TpoR activates JAK2, STAT5 and PI-3-kinase/Akt, 85 but in contrast to EpoR, it is a very strong activator of Shc, of the MAP kinase pathway and of STAT3 (Figure 2a). 83,[86][87][88][89][90] It is interesting that the first consequence of expressing the JAK2 V617F (at lower than physiologic levels in the transgenic model) mutation is to promote platelet formation.…”

Section: Tpor and Mpnsmentioning

confidence: 99%

“…44,56 Interaction between JAK2 and EpoR or TpoR is disrupted by a point mutation (Y114A) in the FERM domain. 47 Expression of the double-mutant JAK2 V617F Y114A in Ba/F3-EpoR cells did not lead to constitutive signaling through STAT5 or to autonomous growth, 57 suggesting that the V617F mutation does not suffice for activation in the absence of the assembly between the JAK2 V617F and a cytokine receptor. It can be noted that members of the JAK family are localized to membranes through recruitment by cytokine receptors, whereas mutations such as Y114A lead to cytosolic localization.…”

Section: Jak2 V617f and Cytokine Receptorsmentioning

confidence: 99%

“…From the C to the N terminus, JH1 represents the kinase domain, JH2 the pseudokinase domain, JH3 and JH4 contain an SH2-like domain and linker regions, whereas JH5-JH7 contain a FERM (band 4.1, ezrin, radixin, moesin) domain 42,43 (Figure 1). JAKs have been proposed to have a bipartite structure and the N terminus is required for binding to receptors, chaperoning and stabilizing them at the surface, [44][45][46][47] whereas the kinase domain is absolutely crucial for signaling. The pseudokinase domain precedes the kinase domain, and because of sequence differences at key residues required for catalysis, it cannot transfer phosphate and thus is catalytically inactive.…”

Section: Constitutive Signaling and Kinase Activity Of Jak2 V617fmentioning

confidence: 99%

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Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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Section: Tpor and Mpnsmentioning

confidence: 99%

Section: Tpor and Mpnsmentioning

confidence: 99%

Section: Tpor and Mpnsmentioning

confidence: 99%

Section: Jak2 V617f and Cytokine Receptorsmentioning

confidence: 99%

Section: Constitutive Signaling and Kinase Activity Of Jak2 V617fmentioning

confidence: 99%

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Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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JAK/STATSignalling and Haematological Malignancies

Constantinescu

Vainchenker

2015

Encyclopedia of Life Sciences

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A major focus of investigation and drug screening efforts started with the discovery of JAK2V617F as a major driver of the BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). An acquired somatic mutation, JAK2V617F , drives 65% of MPNs. Further studies established that these diseases almost always exhibit mutations leading to persistent JAK2‐STAT5 activation. Sequencing of the four mammalian JAKs (Janus kinases) ( JAK1 , JAK2 , JAK3 and TYK2 ) and of the seven STATs (signal transducers and activators of transcriptions) in a variety of cancers identified the pathologic activation of these JAKs and STATs, by mutations in the genes themselves or in upstream or downstream regulators as significant contributors to several haematological and solid malignancies. The development of JAK2, JAK1, JAK3 and TYK2 kinase inhibitors is unfolding with JAK2, JAK1 and JAK3 inhibitors being approved in certain conditions. Altogether, the JAK/STAT pathway became a new gold mine for discovery and therapy in haematological cancers. Key Concepts The JAK/STAT pathway has a central role in cytokine signalling in normal haematopoiesis. The JAK/STAT pathway is frequently pathologically activated by several mechanisms in many types of haematological malignancies. The JAK/STAT pathway can be targeted by small molecules. The JAK/STAT pathway can be pathologically activated by down‐modulation of negative regulators such as phosphatases. Constitutive STAT activation in blood cancers can be the result of several activated kinases, not only JAKs. JAK2 activation is the main mechanismresponsible of the poorprognosis of mostpediatric B‐cell acute lymphoblasticleukemia.

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Eliminative Signaling by Janus Kinases: Role in the Downregulation of Associated Receptors

Carbone

Fuchs

2013

J of Cellular Biochemistry

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Activation of cytokine receptor-associated Janus kinases (JAKs) mediates most, if not all, of the cellular responses to peptide hormones and cytokines. Consequently, JAKs play a paramount role in homeostasis and immunity. Members of this family of tyrosine kinases control the cytokine/hormone-induced alterations in cell gene expression program. This function is largely mediated through an ability to signal towards activation of the signal transducer and activator of transcription proteins (STAT) as well as towards some other pathways. Importantly, JAKs are also instrumental in tightly controlling the expression of associated cytokine and hormone receptors, and, accordingly, in regulating the cell sensitivity to these cytokines and hormones. This review highlights the enzymatic and non-enzymatic mechanisms of this regulation and discusses the importance of the ambidextrous nature of JAK as a key signaling node that integrates the combining the functions of forward signaling and eliminative signaling. Attention to the latter aspect of JAK function may contribute to emancipating our approaches to the pharmacologic modulation of JAKs.

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Janus Kinases Affect Thrombopoietin Receptor Cell Surface Localization and Stability

Cited by 157 publications

References 62 publications

Aberrant signal transduction pathways in myeloproliferative neoplasms

Aberrant signal transduction pathways in myeloproliferative neoplasms

JAK/STATSignalling and Haematological Malignancies

Eliminative Signaling by Janus Kinases: Role in the Downregulation of Associated Receptors

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