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J. Biol. Chem., Vol. 280, Issue 8, 6692-6700, February 25, 2005

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Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation^*

Barbara Ahr¶, Mélanie Denizot, Véronique Robert-Hebmann, Anne Brelot||, and Martine Biard-Piechaczyk**

From the Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS UMR 5121, Institut de Biologie, 4, Bd Henri IV, CS 89508, 34960 Montpellier Cedex 2, France and the ^||Institut Cochin, U567, 22 rue Méchain, 75014 Paris, France

The chemokine SDF-1 transduces G_i-dependent and -independent signals through CXCR4. Activation of Jak2/STAT3, a G_i-independent signaling pathway, which plays a major role in survival signals, is known to be activated after SDF-1 binding to CXCR4 but the domains of CXCR4 involved in this signaling remain unexplored. Using human embryonic kidney HEK-293 cells stably expressing wild-type or mutated forms of CXCR4, we demonstrated that STAT3 phosphorylation requires the N-terminal part of the third intracellular loop (ICL3) and the tyrosine 157 present at the end of the second intracellular loop (ICL2) of CXCR4. In contrast, neither the conserved Tyr¹³⁵ in the DRY motif at the N terminus of ICL2 nor the Tyr⁶⁵ and Tyr⁷⁶ in the first intracellular loop (ICL1) are involved in this activation. ICL3, which does not contain any tyrosine residues, is needed to activate Jak2. These results demonstrate that two separate domains of CXCR4 are involved in Jak2/STAT3 signaling. The N-terminal part of ICL3 is needed to activate Jak2 after SDF-1 binding to CXCR4, leading to phosphorylation of only one cytoplasmic Tyr, present at the C terminus of ICL2, which triggers STAT3 activation. This work has profound implications for the understanding of CXCR4-transduced signaling.

Received for publication, July 27, 2004 , and in revised form, December 21, 2004.

^* This work was supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS) and the University (UM1), and grants from Ensemble contre le SIDA. 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.

Both authors contributed equally to this work.

^¶ Recipient of a fellowship from the Agence Nationale de Recherches sur le SIDA (ANRS).

^** To whom correspondence should be addressed: Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS UMR 5121, Institut de Biologie, 4, Bd Henri IV, CS 89508, 34960 Montpellier Cedex 2, France. Tel.: 33-4-67-60-86-60; Fax: 33-4-67-60-44-20; E-mail: martine.biard{at}univ-montp1.fr.

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