Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage
Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
Sci Signal. 2008 Nov 25;1(47):ra14. doi: 10.1126/scisignal.1161938. Link to article on publisher's site
Ongusaha, Pat P.; Qi, Hank H.; Raj, Lakshmi; Kim, Young-Bum; Aaronson, Stuart A.; Davis, Roger J.; Shi, Yang; Liao, James K.; and Lee, Sam W., "Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage" (2008). Davis Lab Publications. 71.