E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis.

ABSTRACT: The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in macrophages remains unclear. Here, we identify both Cbl-b and c-Cbl (Cbls) as inhibitors of macrophage proliferation and promoters of macrophage apoptosis. Mechanically, we identify that Cbls functions upstream of AKT and Erk to mediate the ubiquitination and degradation of M-CSFR. M-CSF stimulation promotes dimerization and autophosphorylation activation of M-CSFR on the macrophage membrane, thereby activating downstream PI3K-AKT and Erk signaling pathways, leading to different biological effects such as macrophage proliferation and survival. At the same time, the Y559 site of the M-CSFR undergoes autophosphorylation, which can prom

SUBMITTER: Xu F 

PROVIDER: S-EPMC12504418 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature