Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.
Raf-1 serine/threonine protein kinase plays an important role in cell growth, differentiation and cell survival. Recent reports using c-raf-1 gene-knockouts have observed MEK/ERK independent functions of Raf-1 in cell survival and protection from apoptosis. Raf-1 has also been shown to be involved in counteracting specific apoptotic pathways by restraining caspase activation, although the precise mechanism is unknown. XIAP is a potent inhibitor of apoptosis that blocks both the mitochondria and death receptor mediated pathways of apoptosis by directly binding to and inhibiting the initiator and effector caspases. In our efforts to understand the mechanism by which Raf-1 inhibits caspase activation, we discovered a novel interaction between Raf-1 and XIAP. In this study, we describe the physical interaction between Raf-1 and XIAP in vitro and in vivo in mammalian cells. We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo. Additionally, Raf-1 prevents XIAP degradation in response to different apoptotic triggers. Our studies identify XIAP as a new substrate of Raf-1 and provide potentially important insight into mechanisms underlying Raf-1 effects on cell survival.
Tian
Song
S
Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
Mewani
Rajshree R
RR
Kumar
Deepak
D
Li
Bihua
B
Danner
Malika T
MT
Ahmad
Imran
I
Rahman
Aquilur
A
Notario
Vicente
V
Dritschilo
Anatoly
A
Kasid
Usha N
UN
Gokhale
Prafulla C
PC
D017209:Apoptosis; D006801:Humans; D047468:Immunoprecipitation; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000378:metabolism*
D051636:X-Linked Inhibitor of Apoptosis Protein; D019908:Proto-Oncogene Proteins c-raf