Cellular feedback dynamics and multilevel regulation driven by the hippo pathway

Abstract

The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also 'moonlight' by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway.

Keywords: STRIPAK; YAP/TAZ; cell migration; feedback; hippo pathway; mitosis.

Figure 1.. Regulation of mitosis by the Hippo pathway and YAP/TAZ.

(A) Upstream Hippo pathway serine/threonine kinases control activation of LATS1/2 kinases, which in turn directly phosphorylate YAP/TAZ on multiple serine residues and thereby controls YAP/TAZ transcriptional activity though regulating their subcellular localisation. (B) In the nucleus, YAP/TAZ form transcription complexes with various transcription factors to induce expression of cell cycle regulating genes. The cell cycle is further modulated by YAP/TAZ through its interaction with chromatin-modifying proteins, such as nucleosome remodelling and deacetylase (NuRD) complex and histone methyltransferase (HMT) complex, which promote remodelling of chromatin configuration to control gene transcription programmes. (C) LATS1/2 kinases modulate cell cycle exit during late anaphase or telophase through phosphorylation of CDC26 and CTCF. (D) Cyclin-dependent kinases provide an additional level of regulation of mitosis through direct phosphorylation of YAP and TAZ.

Figure 2.. YAP/TAZ activity is central to coordinating cell migration.

Cell migration requires the coordination of various plasma membrane components that link extracellular matrix to the cell cytoskeleton. (A) YAP/TAZ influence the dynamics of the actin cytoskeleton through the expression of Rho GTPase-activating proteins (ARHGAP18, ARHGAP29) and Rho guanine exchange factor (ARHGEF17), which in turn modulates RhoA activity. (B) LAT1/CD98 is a disulfide-linked heterodimer composed of SLC3A2 and SLC7A5 that promotes cell migration and survival by coupling nutrient availability and integrin activity. LAT1/CD98 exports glutamine in exchange of importing amino acids, such as leucine, isoleucine and arginine. SLC3A2 of the LAT1/CD98 heterodimer binds integrins and amplifies integrin-mediated signalling. (C) At the leading edge of the cell, activation of integrin receptors through binding of extracellular matrix (ECM) components promotes focal adhesion complex assembly and the contractile forces generated by the actin cytoskeleton enables movement of the cell. (D) Plasma membrane subdomain caveolae expression is regulated by YAP/TAZ and plays a mechanoprotective role by flattening in response to mechanical forces, such as cellular stretching and osmotic swelling. In migrating cells, caveolae frequently localise to the rear due to low membrane tension. (E) YAP/TAZ-TEAD-mediated transcriptional activity promotes the production of matricellular proteins, such as CYR61 and CTGF. These signalling factors promote cell adhesion, migration and proliferation.