The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway

Abstract

The receptor for activated C-kinase (RACK1), a scaffolding protein that participates in the protein kinase C (PKC) signaling pathway, hasan important role in shuttling active PKCs to its substrate. Indeed, recent studies have revealed that RACK1 hasan important role in tumorigenesis and that enhancement of the feed-forward mechanism of the c-Jun N-terminal kinase (JNK)-Jun pathway via RACK1 is associated with constitutive activation of MEK(MAPK-ERKkinase)-ERK (extracellular signal-regulated kinase)signaling in human melanoma cells. Taken together, RACK1 additionally has a very important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Here, we show that one of the tripartite motif-containing (TRIM) family ubiquitin ligases, TRIM45, is a novel RACK1-interacting protein and downregulates MAPK signal transduction. Importantly, the expression of TRIM45 is induced when growth-promoting extracellular stimuli activate the MAPK signaling pathway, resulting in attenuation of activation of the MAPK pathway. These findings suggest that TRIM45 functions as a member of the negative feedback loop of the MAPK pathway.