TRAF7 in signaling and disease: emerging mechanisms and clinical implications

Tumor necrosis factor receptor-associated factors (TRAFs) are a family of 7 signaling proteins that have regulatory roles in multiple fundamental cellular processes, including immunity, inflammation, apoptosis, permeability, and cell proliferation. TRAF7 is the most recently described with unique features distinguishing it from other TRAFs. It is an E3 ubiquitin ligase that activates MEKK3 and KLF2/4 signaling, inhibits MEK1/2 and c-Myb along with an NF-κβ-modulator, and stabilizes VE-cadherins in cell junctions. Germline mutations in TRAF7 lead to developmental delays and the dysmorphic features associated with TRAF7 syndrome. Somatic TRAF7 mutations are associated with subsets of meningiomas, mesotheliomas, and perineuriomas. Additionally, TRAF7 altered expression is associated with poorer prognoses in hepatocellular carcinoma, breast cancer, and prostate cancer. This review comprehensively describes the physiological roles of TRAF7 and the pathophysiology of clinical conditions with TRAF7 alterations. We highlight important directions for future work to improve our understanding of the mechanisms underlying TRAF7 related disease, identify prognostic biomarkers that help guide clinical decision making, and potentially identify novel therapeutic targets to expand our treatment options for these patients.