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, were essential for the interaction with phosphatidylserine in the PM. This interaction favored the cooperative binding of DA-Raf to active Ras, which predominated over that of Raf proteins, leading to the stable PM association of DA-Raf. Consequently, DA-Raf exerts its dominant-negative function on Raf proteins to prevent the Ras-ERK pathway.

https://opac.ll.chiba-u.jp/da/curator/900123437/

Life Science Alliance LLC

Journal Article

25751077

41120211

Life Science Alliance

8

12

e202503300

2025

https://doi.org/10.26508/lsa.202503300

eng

publisher

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