[Show abstract][Hide abstract] ABSTRACT: Ras activation is common to many human cancers and promotes cell proliferation and survival by initiating multiple signaling cascades. Accordingly, Ras-transformed cells are generally considered too resourceful to become addicted to a single effector. In contrast to this tenet, we now demonstrate an absolute, cell autonomous requirement for Raf-1 in the development and maintenance of Ras-induced skin epidermis tumors. Mechanistically, Raf-1 functions as an endogenous inhibitor dimming the activity of the Rho-dependent kinase Rok-alpha in the context of a Ras-induced Raf-1:Rok-alpha complex. Raf-1-induced Rok-alpha inhibition allows the phosphorylation of STAT3 and Myc expression and promotes dedifferentiation in Ras-induced tumors. These data link the Raf-1:Rok-alpha complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis.
Cancer cell 09/2009; 16(2):149-60. DOI:10.1016/j.ccr.2009.06.008 · 23.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Raf kinases relay signals inducing proliferation, differentiation, and survival. The Raf-1 isoform has been extensively studied
as the upstream kinase linking Ras activation to the MEK/ERK module. Recently, however, genetic experiments have shown that
Raf-1 plays an essential role in counteracting apoptosis, and that it does so independently of its ability to activate MEK.
By conditional gene ablation, we now show that Raf-1 is required for normal wound healing in vivo and for the migration of
keratinocytes and fibroblasts in vitro. Raf-1–deficient cells show a symmetric, contracted appearance, characterized by cortical
actin bundles and by a disordered vimentin cytoskeleton. These defects are due to the hyperactivity and incorrect localization
of the Rho-effector Rok-α to the plasma membrane. Raf-1 physically associates with Rok-α in wild-type (WT) cells, and reintroduction
of either WT or kinase-dead Raf-1 in knockout fibroblasts rescues their defects in shape and migration. Thus, Raf-1 plays
an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration.
The Journal of Cell Biology 03/2005; 168(6):955-964. DOI:10.1083/jcb.200409162 · 9.83 Impact Factor