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Originally published In Press as doi:10.1074/jbc.M102679200 on May 21, 2001

J. Biol. Chem., Vol. 276, Issue 33, 31349-31356, August 17, 2001
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The Nck-interacting Kinase (NIK) Phosphorylates the Na+-H+ Exchanger NHE1 and Regulates NHE1 Activation by Platelet-derived Growth Factor*

Weihong YanDagger , Keith Nehrke§, Jimmy ChoiDagger , and Diane L. BarberDagger ||

From the Departments of Dagger  Stomatology and  Surgery, University of California, San Francisco, 94143 and § Center for Oral Biology, University of Rochester, Rochester, New York 14642

NIK, a recently identified Nck-interacting kinase, acts upstream of the MEK kinase MEKK1 to activate the c-Jun N-terminal kinase JNK. We now show that NIK binds to and divergently activates the plasma membrane Na+-H+ exchanger NHE1. In a genetic screen, NHE1 interacted with NIK at a site N-terminal (amino acids 407-502) to the Nck-binding domain, and this site is critical for its association with NHE1 in vivo. NIK also phosphorylates NHE1; however, the phosphorylation sites, which are distal to amino acid 638, are distinct from the NIK-binding site on NHE1 (amino acids 538-638). Expression of wild-type, but not a kinase-inactive, NIK in fibroblasts increased NHE1 phosphorylation and activity. The kinase domain of NIK, however, was not sufficient for this response in vivo. Full phosphorylation and activation of NHE1 required both the kinase and the NHE1-binding domains of NIK, suggesting that the NHE1-binding site functions as a targeting signal. The functional significance of an interaction between NIK and NHE1 was confirmed by the ability of a kinase-inactive NIK to selectively inhibit activation of NHE1 by platelet-derived growth factor but not by thrombin. Moreover, although NIK activates JNK through a mechanism dependent on MEKK1, it phosphorylated and activated NHE1 independently of MEKK1. These findings indicate that NIK acts downstream of platelet-derived growth factor receptors to phosphorylate and activate NHE1 divergently of its activation of JNK.

* This work was supported by National Institutes of Health Grants GM47413 and DK40259 (to D. L. B.) and in part by NIH Grant DE08921 (to K. N.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| Supported by an Established Investigator award from the American Heart Association. To whom correspondence should be addressed: Box 0512, University of California, 513 Parnassus Ave., San Francisco, CA 94143. Tel.: 415-476-3764; Fax: 415-502-7338; E-mail: barber@itsa.ucsf.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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