Proceedings of the Singapore National Academy of Science

WW-domain binding protein 2 (WBP2) was first discovered as a ligand of the WW-domain of Yes-associated Protein (YAP). A decade after its discovery, our laboratory implicated WBP2 in breast cancer development. Since then, WBP2 had also been shown to be involved in other types of cancer, such as glioma, liver and skin cancer. The oncogenic properties of WBP2 are mediated by several oncogenic signalling pathways, including EGFR, PI3K/Akt, ER, Wnt, and Hippo signalling pathways. Recently, WBP2 was demonstrated to play roles in diseases other than cancer, such as infertility and deafness. In the near future, we envisage a growing body of literature surrounding the role of WBP2 in more cancer types and signalling pathways.

Scaffold proteins are critical regulators of important cell signaling pathways. Though scaffolds are not stringently defined in meaning, they are known to interact with numerous components of a signaling pathway, binding and bridging them into distinct and functional complexes. They control signal transduction and assist the localization of pathway components (organized in complexes) to definite regions of the cell such as the endosomes, plasma membrane, the cytoplasm, mitochondria, Golgi, and the nucleus. Years of research in this field have revealed the versatility of this class of protein and the important role it plays in maintaining the normal functions of the human body. Here, we discuss the role of several scaffold proteins which are implicated in important signaling pathways that play important roles in cardiac diseases, metabolic diseases, neurological disorders, and cancer. Their versatility and functions in human diseases make them attractive drug targets, several of which have been investigated in clinical trials. Future studies of scaffold proteins should give us an in-depth knowledge of how cell signaling works in normal and pathological conditions and would offer avenues to disrupt harmful cellular pathways to circumvent diseases.

A recent large genome-wide association meta-analysis revealed that the human WWOX gene is regarded as one of the five newly identified risk factors for Alzheimer’s disease (AD). However, this study did not functionally characterize how WWOX protein deficiency affects AD initiation, progression and neurodegeneration. In this review, evidence and perspectives are provided regarding how WWOX works in limiting neurodegeneration. Firstly, loss of WWOX/Wwox gene leads to severe neural diseases with degeneration, metabolic disorder and early death in the newborns. Downregulation of pY33-WWOX may start at middle ages, and this leads to slow aggregation of a cascade of proteins, namely TRAPPC6A$\mathrm{\Delta }$, TIAF1 and SH3GLB2, that leads to amyloid-beta (A$\beta$) formation and tau tangle formation in old-aged AD patients. Secondly, functional antagonism between tumor suppressors p53 and WWOX may occur in vivo, in which p53-mediated inflammation is blocked by WWOX. Loss of balance in the functional antagonism leads to aggregation of pathogenic proteins for AD such as tau and A$\beta$ in the brain cortex and hippocampus. Thirdly, downregulation of pY33-WWOX is accompanied by upregulation of pS14-WWOX. The event frequently correlates with enhanced AD progression and cancer cell growth in vivo. A small peptide Zfra4-10 dramatically suppresses pS14-WWOX and restores memory loss in triple transgenic (3xTg) mice, and inhibits cancer growth in mice as well. Finally, a supporting scenario is that WWOX deficiency induces enhanced cell migration and loss of cell-to-cell recognition. This allows the generation of neuronal heterotopia and associated epileptic seizure in WWOX-deficient newborn patients.

The zebrafish has been an increasingly popular animal model for human diseases as it offers the combined advantages compared to various animal models and cell based assays; in particular, the feasibility of high throughput studies as an economical vertebrate model. In this past decade, we and several other laboratories have developed various hepatocellular carcinoma (HCC) models using the zebrafish and demonstrated the conservation of HCC between zebrafish and human at both histopathological and molecular levels. In this review, we focus on the conservation of signal transductions during hepatocarcinogenesis between zebrafish and human. Based on existing zebrafish HCC models, indeed many alterations of signal pathways that cause human liver cancers can also result in HCC in zebrafish, such as Ras pathway, EGFR pathway, Wng/β-catenin pathway, TGF-β pathway, PI3K/AKT pathway, JAK/STAT pathway, Hippo pathway, src tyrosine kinase pathway, etc. In future, zebrafish may be used for better quantification of signaling molecules and thus to aid development of more effective therapeutic methods.