TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis.

TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis. J Clin Invest. 2018 May 01;: Authors: Singh R, Karri D, Shen H, Shao J, Dasgupta S, Huang S, Edwards DP, Ittmann MM, O'Malley BW, Yi P Abstract Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of wild type RTKs plays an important role in driving cancer progression. However, the underlying mechanisms of how RTKs drive prostate cancer remain incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27 and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine auto-phosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed NGF-stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TR...
Source: Clinical Prostate Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research