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, has an important role in shuttling active PKCs to its substrate. Indeed, recent studies have revealed that RACK1 has an 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-ERK kinase)-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.

TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination

“…As PI3K-Akt and Ras-MAPK signaling pathway are the most frequently activated signaling pathways involved in gliomagenesis and TRIM45 was also reported to be associated with PKC-mediated modulation of the ERK-JNK and NF- κ B signaling pathway, 19, 20 we examined the phosphorylation status of AKT, ERK, JNK, p38, and IKK β in TRIM45-overexpressing or TRIM45 KO glioma cells. We did not detect any change in the phosphorylation status of all the kinases examined, regardless of whether the expression of TRIM45 was upregulated or downregulated (Supplementary Figures 7A and B), suggesting that TRIM45 does not affect the PI3K/AKT, MAPK, and NF- κ B signaling pathways in glioma cells.…”

“…As TRIM45 is an E3 ligase, 19 we next determined whether TRIM45 affects p53 stability via ubiquitination. First, we found that TRIM45 promoted the polyubiquitination of p53 in a dose-dependent manner (Figure 6a).…”

“…TRIM45 was reported to negatively regulate the MAPK signaling pathway by inhibiting RACK1/PKC complex formation. 18, 19 It also negatively regulates NF- κ B signaling. 20 Although TRIM45 mRNA is highly expressed in the brain of human adult and embryonic tissues, 18 its function in primary CNS tumors has not been investigated yet.…”

Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

“…15 It has been shown that the PRYSPRY region of TRIM proteins is involved in molecular recognition and has antiviral activity. 17 Among the TRIM protein family, TRIM39 and TRIM45 have been reported to modulate inflammatory signaling through inhibition of the nuclear factor kB (NF-kB)-and protein kinase C-mediated pathways, 18,19 whereas TRIM40 is protective in inflammation-associated carcinogenesis in the gastrointestinal tract. 20 Moreover, TRIM22 variants are involved in early and adult-onset of IBDs through regulating the NOD2 signaling pathway.…”

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

“…Cells stably overexpressing 3×Flag-RNF207 were established by a retroviral expression system using pMX-puro with puromycin (8 µg ml -1 , Sigma) selection as described previously [26].…”