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J. Biol. Chem., Vol. 280, Issue 51, 41893-41899, December 23, 2005
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JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation
CROSS-TALK WITH IGF1 RECEPTOR*
12135
From the
Ludwig Institute for Cancer Research, Brussels B-1200, Belgium, the Christian de Duve Institute for Cellular Pathology and the MEXP Unit, Université Catholique de Louvain, Brussels B-1200, Belgium, and the ¶INSERM U362, Institut Gustave Roussy, 94805 Villejuif Cedex, France
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.
Received for publication, August 22, 2005 , and in revised form, October 17, 2005.
* This work was supported in part by grants from La Ligue Nationale contre le Cancer (to W. V., Équipe Labelisée 2003), la Fédération Belge contre le Cancer (to J.-B. D. and S. N. C.), and the"de Hovre"Foundation and the Fonds National de la Recherche Scientifique (F.N.R.S.), Belgium (Mandat d'Impulsion) (to S. N. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
2 Supported by a Daimler-Benz Ph.D. fellowship, an exchange Marie Curie fellowship and a F.N.R.S. Télévie fellowship
3 Supported by the Lacroix Christian de Duve Institute of Cellular Pathology postdoctoral fellowship.
4 Supported by an interface contract between INSERM and IGR.
5 A Research Associate of the F.N.R.S., Belgium. To whom correspondence should be addressed. E-mail: stefan.constantinescu{at}bru.licr.org.
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