MARCH7 As E3 Ubiquitin Ligase Mediates ?-catenin Ubiquitin Proteasome Degradation

Wnt/?-catenin signaling pathway plays a key role in tumorigenesis,development,invasion and metastasis.?-catenin and E-cadherin form a complex to regulate cell junction and cytoskeleton.At the same time,in the regulation of signaling pathways,?-catenin transfers into nucleus to perform transcriptional functions,thereby promoting the expression of tumor-related genes.At present,the regulation of ?-catenin,especially the study of protein stability,is relatively clear.However,due to the mutant possibility of its regulator,the mechanism of non-classical degradation of ?-catenin seems to be a promising research direction of ?-catenin-induced carcinoma.In this paper,we found a degradation pathway of ?-catenin independent of APC/Axin complex from a mutant cell line.The E3 ligase MARCH7 was found by mass spectrometry analysis.We unraveled that MARCH7 interacts with ?-catenin,and knocking down MARCH7 can increase the protein level of ?-catenin.Overexpression of MARCH7 increases the ubiquitination degradation of ?-catenin.Through the online database,it was found that Y315 of MARCH7 was phosphorylated.After Y315 is mutated to F,MARCH7 cannot degrade ?-catenin and lose the interact ability with ?-catenin.Bioinformatics analysis showed that SRC tyrosine kinase was predicted to be an upstream kinase.In mutant cell lines,SRC activation site Y416 phosphorylation is up-regulated,and MARCH7 interacts with SRC.Analysis of the TCGA database confirmed that the high expression of MARCH7 had a positive effect on the survival of patients with renal clear cell carcinoma,and that the expression of MARCH7 in patients with advanced tumors was significantly lower than that in the normal group or early patients.Therefore,it suggested that MARCH7 is important for patients with renal clear cell carcinoma and a marker for prognosis of these patients.