Regulation of YAP and TAZ by Epithelial Plasticity

Abstract

The Hippo transducers YAP and TAZ are central mediators of organ growth and tumorigenesis, regulating cell proliferation, differentiation, and epithelial stemness. In this chapter, we summarize recent fi ndings linking the activation of YAP and TAZ to the cell's structural and architectural features, such as cell polarity, cell shape, cell adhesion, and cytoskeletal dynamics. We examine how epithelial "plasticity" induced by epithelial-to-mesenchymal transition (EMT) promotes "Cancer Stem Cell" identity and YAP/TAZ activation, and discuss the role of TAZ as molecular determinant of self-renewal and tumor-seeding potentials in cancer cells. YAP and TAZ activation can also induce EMT, generating a self-sustaining loop. We then place special emphasis on biomechanical cues as regulators of epithelial plasticity, and as dominant regulators of YAP and TAZ nuclear localization and transcriptional activities. This regulation is mediated by physical forces, such as rigidity of the extracellular matrix, and tension of the actomyosin cytoskeleton. These mechanical signals hold in shape individual cells and whole tissues, and are severely disturbed in cancer. In sum, we highlight new mechanisms of YAP and TAZ regulation by cell polarity and mechanical cues. This potentially adds a new dimension to our understanding of physiology and tumorigenesis, whereby the behavior of individual cells is dictated by the integration of information about tissue architecture and mechanics mediated by YAP and TAZ.

Interaction proteome of human Hippo signaling: modular control of the co‐activator YAP1

“…But what are the molecules and mechanisms that link processes relevant for tissue integrity such as mechanotransduction or cell polarity to growth control by the Hpo pathway? Recent genetic and biochemical data on individual pathway components first revealed links between the Hpo pathway and proteins at the cellular membrane and intercellular junction (Piccolo & Cordenonsi, 2013). This suggests close links between epithelial plasticity, cell polarity and growth control by Yki/YAP (Piccolo & Cordenonsi, 2013).…”

“…Recent genetic and biochemical data on individual pathway components first revealed links between the Hpo pathway and proteins at the cellular membrane and intercellular junction (Piccolo & Cordenonsi, 2013). This suggests close links between epithelial plasticity, cell polarity and growth control by Yki/YAP (Piccolo & Cordenonsi, 2013). However, most of these recent insights were obtained on isolated Hpo pathway components studied in different cellular contexts using different biochemical approaches, which complicates the integration of such information into coherent models of tissue growth.…”

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

“…This suggests that although YAP/TAZ are avid coordinators of EMT, they are not necessarily responsible for the reversion of tumor cells to an epithelial phenotype. However, in turn both are indispensable for EMT and required for MET [ 78 , 79 ]. In this sense, the evidence presented indicates that YAP/TAZ can induce changes in the phenotype of tumor cells and produce EMT depending on their gene expression levels and cellular context, creating a bidirectional link between the activation of these transcription cofactors and the maintenance of the EMT genetic program.…”

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

“…Interestingly, further stratification of tumor phenotype into a molecular classification revealed a striking association of TAZ expression to the basal phenotype (70.8% TAZ-positive, Table 1). Given the established link between TAZ/YAP and EMT (Piccolo & Cordenonsi 2013), we assessed TAZ expression in an independent tumor set of 15 MBC. Interestingly, 11 out of 12 MBC with histological evidence of EMT toward spindle cell or heterologous sarcomatous differentiation showed TAZ expression; in contrast, two out of three MBC with squamous differentiation were TAZ-negative (Table 2).…”

“…The final downstream transducers of the Hippo pathway are the transcriptional coactivators TAZ and YAP, both of which contribute to epithelial-mesenchymal transition (EMT)-mediated cancer progression. A bidirectional relationship between YAP/TAZ and EMT, wherein a loss of cell polarity and cell-cell junctions induces the activation of both factors that in turn sustain the EMT program, has been proposed (Piccolo & Cordenonsi 2013). The activity of TAZ/YAP is mainly inhibited by phosphorylation mediated by the LATS1/2 kinases, which in turn are activated by the MST1/2 kinases (homologues of Drosophila Hippo).…”