cRaf

cRaf, also known as Raf-1, is a cytoplasmic serine/threonine-protein kinase encoded by the RAF1 gene in humans. It is one of the three Raf kinases, alongside A-Raf and B-Raf, that operate within the MAP kinase signaling cascade.

In the canonical Ras–Raf–MEK–ERK pathway, active Ras-GTP recruits Raf-1 to the plasma membrane, where it becomes activated through conformational changes and phosphorylation. Activated Raf-1 then phosphorylates and activates MEK1/2, which in turn activates ERK1/2. This signaling cascade regulates transcription, cell proliferation, differentiation, and survival.

Regulation of Raf-1 is complex and tightly controlled. Its N-terminal regulatory region contains autoinhibitory elements, and phosphorylation at certain sites promotes binding of 14-3-3 proteins, stabilizing an inactive state. Dimerization, including heterodimerization with B-Raf, is often required for full signaling output. Feedback from ERK can further modulate Raf-1 activity, helping to shape the duration and intensity of signaling.

Structure and expression: Raf-1 is a ~648-amino-acid protein predominantly located in the cytoplasm. It is widely expressed and is the best-characterized member of the Raf kinase family after B-Raf.

Clinical relevance: Alterations in RAF1, including amplifications, rearrangements, or activating mutations, have been observed in various cancers, though B-Raf mutations are more common in many tumor types. Therapeutic approaches include MEK inhibitors and broader Raf inhibitors; the effects of Raf inhibitors can be complex due to feedback mechanisms and dimerization dynamics.