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JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation - Cross-talk with IGF1 receptor

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Staerk, Judith [UCL] Kallin, Anders [UCL] Demoulin, Jean-Baptiste [UCL] Vainchenker, William Constantinescu, Stefan N. [UCL]

The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2005
Language Anglais
Journal information "Journal of Biological Chemistry" - Vol. 280, no. 51, p. 41893-41899 (2005)
Peer reviewed yes
Publisher Amer Soc Biochemistry Molecular Biology Inc (Bethesda)
issn 0021-9258
e-issn 1083-351X
Publication status Publié
Affiliation UCL - Autre
Links
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Bibliographic reference Staerk, Judith ; Kallin, Anders ; Demoulin, Jean-Baptiste ; Vainchenker, William ; Constantinescu, Stefan N.. JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation - Cross-talk with IGF1 receptor. In: Journal of Biological Chemistry, Vol. 280, no. 51, p. 41893-41899 (2005)
Permanent URL http://hdl.handle.net/2078.1/38933