Abstract
Simple SummaryThe conserved Hippo pathway regulates cell proliferation and apoptosis via a complex interplay of transcriptional activities, post-translational protein modifications, specific protein–protein interactions and cellular transport processes. Deregulating this highly balanced system can lead to hyperproliferation, organ overgrowth and cancer. Although WWC proteins are known as components of the Hippo signaling pathway, their association with tumorigenesis is often neglected. This review aims to summarize the current knowledge on WWC proteins and their contribution to Hippo signaling in the context of cancer.The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms.
Highlights
The presence of two aminoterminal WW domains within the WWC proteins mediating large tumor suppressor kinases 1/2 (LATS1/2) interaction and their common carboxyterminal atypical protein kinase C (aPKC)-binding motif could theoretically allow the formation of a trimeric LATS1/2–WWC–aPKC complex
Our knowledge on the impact of a deregulated Hippo pathway in cancer is constantly growing and the number of publications dealing with this aspect is increasing from year to year
The identification of novel regulatory mechanisms affecting gene transcription, epigenetic gene silencing, miRNA-mediated translation control, dynamic protein–protein interactions and post-translational protein modifications indicate the huge complexity of Hippo signaling under physiological and pathological conditions
Summary
The Hippo signaling pathway and its impact on cell proliferation, apoptosis and organ growth have been examined with increasing interest within the last two decades (reviewed in [1,2,3]). Unphosphorylated YAP and TAZ are able to enter the nucleus and to bind to a group of transcription factors, including TEA domain family member 1 (TEAD1). This interaction, in turn, induces the expression of pro-proliferative genes (reviewed in [1,2,3]). It can be concluded that the activity of the MST1/2 and LATS1/2 kinases as well as the phosphorylation status of YAP and TAZ constitute the main regulatory switches controlling Hippo signaling. Hippo signaling is continuously growing, consisting of cytoskeleton proteins, membrane receptors, enzymes and scaffolding proteins (reviewed in [1,2,3,8])
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