Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules

Abstract

Recent findings indicate that the WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. WWOX protein mediates multiple signaling networks that suppress carcinogenesis through binding of its first WW domain to various cancer-associated proteins, i.e., p73, AP-2γ, and others. Although the tumor suppressor property of WWOX is inarguable, WWOX is not inactivated in the manner characteristic of the canonical Knudson hypothesis. Impairment of both alleles of WWOX is thought to be a rare event, only occurring in a few cancer cell lines. How is the tumor suppressor function of WWOX impaired in cancer cells? Recent advances highlight that a small transmembrane protein possessing a PPxY motif, called TMEM207, and its relatives are aberrantly expressed in various cancer cells and hinder the tumor suppressor function of WWOX through inhibiting its WW domain. Here, we review the recent findings related to the pathobiological properties of TMEM207 and its relatives based on clinicopathological and experimental pathological studies.

Keywords: PPxY motif; WW domain; WWOX; aerobic glycolysis; cancer.

Figure 1

Protein sequence of Shisa/Shisa like family proteins and TMEM207. (A) Fundamental protein structure of Shisa/Shisa-like family proteins proposed by Pei and Grishin (9). In addition, we note the W, Y or W, F or I, W protein sequence at juxta-transmembrane domain. (B) Graphical depiction of homologous regions of TMEM207 and VOPP1. Note the PPxY motif, which binds WW-domain, at the C-terminus.

Figure 2

Physiological aspects of TMEM207. At the endoplasmic reticulum, TMEM207 participates in the quality control of intelectin-1, which recognizes glycan epitopes found exclusively on microbes and plays a role in intestinal innate immunity through assisting phagocytic clearance of microorganisms. TMEM207 may participate in intestinal innate immunity by promoting the proper secretion of intelectin-1. TMEM207 and its relatives harbor a canonical PPxY motif to bind the WW domain of WWOX.