Rapidly Accelerated Fibrosarcoma protein dimers (RAF dimers)

Rapidly Accelerated Fibrosarcoma (RAF) protein dimers are quaternary protein structures formed by the association of ARAF, BRAF, or CRAF isoforms, serving as essential mediators in the Mitogen-Activated Protein Kinase (MAPK/ERK) signaling pathway [1]. Dimerization is a physiological requirement for RAF activation, typically initiated by the recruitment of RAF monomers to the plasma membrane by active RAS-GTP [2]. In many human cancers, including melanoma and colorectal carcinoma, oncogenic mutations in RAS or specific non-V600 BRAF mutations stabilize these dimers, leading to constitutive signaling that drives malignant cell proliferation and survival [3]. While early BRAF inhibitors like vemurafenib were designed to target monomeric BRAF V600E, they often cause paradoxical pathway activation in RAS-mutant cells by promoting RAF dimerization [4]. Consequently, modern drug development focuses on next-generation pan-RAF inhibitors and dimer-breakers that can effectively inhibit the active dimeric state, providing a critical therapeutic approach for patients with RAS-driven or inhibitor-resistant tumors [5]. Sources: [1] Lavoie, H., & Therrien, M. (2015) Nature Reviews Molecular Cell Biology; [2] Hu, J., et al. (2013) Cell; [3] Karoulia, Z., et al. (2017) Nature Reviews Cancer; [4] Hatzivassiliou, G., et al. (2010) Nature; [5] Yao, Z., et al. (2015) Nature.

Other names

RAF homodimersRAF heterodimersBRAF-CRAF dimersBRAF-BRAF dimersCRAF-CRAF dimersARAF-BRAF dimersARAF-CRAF dimers

Inhibition of the kinase activity of RAF subunits within the dimeric complex or prevention of the dimerization process itself to block downstream MEK/ERK signaling.