title: Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage.
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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Pat P
authors.initials: PP
authors.lastname: Ongusaha
authors.forename: Hank H
authors.initials: HH
authors.lastname: Qi
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Raj
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011832:Radiation Injuries / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485750:MAPK8IP3 protein, human; D009419:Nerve Tissue Proteins; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases