Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage.
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.
Ongusaha
Pat P
PP
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Qi
Hank H
HH
Raj
Lakshmi
L
Kim
Young-Bum
YB
Aaronson
Stuart A
SA
Davis
Roger J
RJ
Shi
Yang
Y
Liao
James K
JK
Lee
Sam W
SW
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*
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