DA-Raf synergistically binds to the plasma membrane and Ras to suppress ERK signaling.

ABSTRACT: The small GTPase Ras on the plasma membrane (PM) activates the ERK pathway (Raf-MEK-ERK signaling pathway) to regulate a variety of cellular, physiological, and pathological events. DA-Raf1 (DA-Raf) is a splicing isoform of A-Raf and contains the Ras-binding domain and the Cys-rich domain but lacks the conserved region 2 (CR2) and CR3 containing the kinase domain. Accordingly, DA-Raf dominant-negatively regulates Raf proteins to prevent the Ras-ERK pathway. We elucidate here the mechanisms of how DA-Raf conducts its dominant-negative function on Raf proteins. Because DA-Raf lacks the CR2 and CR3, it was incapable of adopting the autoinhibitory closed conformation and thereby favorable for PM localization. Basic amino acids in DA-Raf Ras-binding domain, and those in the Cys-rich domain, wer

SUBMITTER: Takano K 

PROVIDER: S-EPMC12540644 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature