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Sci. Signal., 25 November 2008
Vol. 1, Issue 47, p. ra14
[DOI: 10.1126/scisignal.1161938]

RESEARCH

Identification of ROCK1 as an Upstream Activator of the JIP-3 to JNK Signaling Axis in Response to UVB Damage

Pat P. Ongusaha1, Hank H. Qi2, Lakshmi Raj1, Young-Bum Kim3, Stuart A. Aaronson4, Roger J. Davis5, Yang Shi2, James K. Liao6, and Sam W. Lee1*

1 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, 13th Street, Building 149, Charlestown, MA 02129, USA.
2 Department of Pathology, Harvard Medical School, NRB 854, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
3 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
4 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
5 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6 Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, 65 Landsdowne Street, Room 275, Cambridge, MA 02139, USA.

Abstract: Although apoptosis triggered by ultraviolet B (UVB)–mediated activation of the c-Jun N-terminal kinase (JNK) pathway is mediated by both intrinsic and extrinsic pathways, the mechanism of initiation of JNK activation remains obscure. Here, we report the characterization of the JNK-interacting protein 3 (JIP-3) scaffolding protein as an interacting partner of Rho-associated kinase 1 (ROCK1), as determined by tandem affinity protein purification. Upon UVB-induced stress in keratinocytes, ROCK1 was activated, bound to JIP-3, and activated the JNK pathway. Moreover, phosphorylation of JIP-3 by ROCK1 was crucial for the recruitment of JNK. Inhibition of the activity of ROCK1 in keratinocytes resulted in decreased activation of the JNK pathway and thus a reduction in apoptosis. ROCK1+/– mice exhibited decreased UVB-mediated activation of JNK and apoptosis relative to wild-type mice. Our findings present a new molecular mechanism by which ROCK1 functions as a UVB sensor that regulates apoptosis, an important event in the prevention of skin cancer.

* To whom correspondence should be addressed. E-mail: swlee{at}partners.org

Citation: P. P. Ongusaha, H. H. Qi, L. Raj, Y.-B. Kim, S. A. Aaronson, R. J. Davis, Y. Shi, J. K. Liao, S. W. Lee, Identification of ROCK1 as an Upstream Activator of the JIP-3 to JNK Signaling Axis in Response to UVB Damage. Sci. Signal. 1, ra14 (2008).

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