C-Raf kinase Overview
C-Raf kinase, also known as RAF1 or Raf-1 proto-oncogene serine/threonine kinase, is a key serine/threonine-protein kinase in the RAF family. It acts as a principal component of the mitogen-activated protein kinase (MAPK) pathway—specifically the ERK1/2 signaling cascade—serving as a MAP3K that initiates downstream signaling events critical for cell fate decisions. Its activation requires binding to active GTP-bound Ras at cellular membranes, conformational change from closed/inactive to open/active state upon Ras binding, and phosphorylation at specific sites. Aberrant regulation or overexpression of c-Raf is implicated in various cancers and developmental disorders. Resistance mechanisms against BRAF inhibitors often involve compensatory activation of C-Raf. Inhibitors targeting RAF kinases can block MEK/ERK activation but may paradoxically increase signaling under certain conditions.
Mechanism of Action
RAF kinase inhibitors block MEK/ERK activation.
Biological Functions
Disease Associations
Safety Considerations
- Paradoxical increase in signaling under certain conditions due to complex feedback/dimerization mechanisms involving wild-type versus mutant forms.
- Effectiveness of targeting only c-Raf remains debated because both its kinase-dependent and independent functions contribute variably depending on tumor context—especially relevant for KRAS-mutant tumors where c-Raf’s non-catalytic roles may be essential.