WWOX gene and gene product: tumor suppression through specific protein interactions

Abstract

The WWOX gene, an archetypal fragile gene, encompasses a chromosomal fragile site at 16q23.2, and encodes the approximately 46-kDa Wwox protein, with WW domains that interact with a growing list of interesting proteins. If the function of a protein is defined by the company it keeps, then Wwox is involved in numerous important signal pathways for bone and germ-cell development, cellular and animal growth and death, transcriptional control and suppression of cancer development. Because alterations to genes at fragile sites are exquisitely sensitive to replication stress-induced DNA damage, there has been an ongoing scientific discussion questioning whether such gene expression alterations provide a selective advantage for clonal expansion of neoplastic cells, and a parallel discussion on why important genes would be present at sites that are susceptible to inactivation. We offer some answers through a description of known WWOX functions.

Figure 1. Alteration of Wwox expression in common human cancers

Summary of studies reporting loss or reduction of Wwox expression or alterations to WWOX alleles in cancers of many organs of both males and females. AdCa: Adenocarcinoma; Ca: Carcinoma; HCC: Hepatocellular carcinoma; NSCLC: Non-small-cell lung cancer; PrCa: Prostrate cancer; PTC: Papillary thyroid carcinoma.

Figure 2. Wwox participates in multiple cancer-associated signal pathways through protein–protein interactions

Wwox-partner protein interactions in signal pathways are affected by absence or reduction of Wwox expression. Wwox, via its first WW domain, binds PPxY domain-containing proteins and sequesters them in the cytoplasm, suppressing their transcriptional transactivation functions. Examples of these proteins are Ap2α/γ, p73, ICD of ErbB4 and juxtamembrane fragments of Met (CTF). Moreover, Wwox competes with other WW domain-containing proteins for binding to these interactor proteins; for example, Wwox outcompetes Yap for binding to the ErbB4 ICD and inhibits the Yap-induced ICD activity. In addition to sequestering the active ErbB4 and Met fragments, Wwox binds and stabilizes the full-length forms of these proteins. In osteoblasts and probably in some solid cancer cells, Wwox associates with chromatin-bound Runx2 and suppresses its transactivation function. Wwox also regulates the Wnt–β-catenin signaling pathway by preventing the nuclear import of the Dvl protein. In response to UV stress, the Wwox–Jun complex is significantly enhanced. This sequesters Jun in the cytoplasm, suppressing its transcriptional activity mediated through Jnk activation. According to work in Chang’s laboratory, Jnk1 may also bind to murine Wwox, blocking cell-cycle progression and inhibiting Wwox-mediated cell death [79]. Wwox physically interacts with ezrin after PKA-mediated phosphorylation of ezrin, facilitating proton pump H,K-ATPase recruitment to apical membrane during the parietal cell activation. It is likely that there is tissue specificity of individual pathways in signaling growth, stasis, cell or substrate interaction, metabolic activity, differentiation or cell death, with dependence on WW domain networks active in particular organs or contexts. CKI: Casein kinase; CTF: C-terminal fragment; GSK: Glycogen synthase kinase; ICD: Intracellular domain; JNK: Jun N-terminal kinase; PKA: Protein kinase A.