G protein-coupled receptors: bridging the gap from the extracellular signals to the Hippo pathway

Abstract

The Hippo pathway is crucial in organ size control, whereas its dysregulation contributes to organ degeneration or tumorigenesis. The kinase cascade of MST1/2 and LATS1/2 and the coupling transcription co-activators YAP/TAZ represent the core components of the Hippo pathway. Extensive studies have identified a number of upstream regulators of the Hippo pathway, including contact inhibition, mechanic stress, extracellular matrix stiffness, cytoskeletal rearrangement, and some molecules of cell polarity and cell junction. However, how the diffuse extracellular signals regulate the Hippo pathway puzzles the researchers for a long time. Unexpectedly, recent elegant studies demonstrated that stimulation of some G protein-coupled receptors (GPCRs), such as lysophosphatidic acid receptor, sphingosine-1-phosphate receptor, and the protease activated receptor PAR1, causes potent YAP/ TAZ dephosphorylation and activation by promoting actin cytoskeleton assemble. In this review, we briefly describe the components of the Hippo pathway and focus on the recent progress with respect to the regulation of the Hippo pathway by GPCRs and G proteins in cancer cells. In addition, we also discuss the potential therapeutic roles targeting the Hippo pathway in human cancers.

Regulation of TAZ in cancer

“…GPCRs represent the largest family of membrane receptors in mammals and mediate numerous signals during physiological and pathological conditions. The link between GPCRs and the Hippo signaling pathway provides novel insights into the regulation of TAZ, implying the multiple functions of TAZ in different cell types and different circumstances (Yu & Guan, 2013 ; Zhou et al, 2015b ). G proteins and GPCRs are frequently altered in human cancers (Kan et al, 2010 ; O’Hayre et al, 2013 ).…”

Role of Yes-associated protein in cancer: An update

“…GPCR activates YAP by inducing F-actin polymerization through Rho GTPase, and thus inhibit LATS kinase activity ( 7 ). There are two types of ligands-agonists that activate GPCR: i) Lipoprotein(a), sphingosine-1-phosphate and thrombin, which inhibit cell proliferation; and ii) glucagon and epinephrine, which induce cell proliferation ( 8 ) ( Fig. 2 ).…”

Repair Injured Heart by Regulating Cardiac Regenerative Signals

“…These pathway components are enriched with WW domains and their cognate proline-rich interacting motifs provide an efficient signaling mechanism to sense upstream input and start off the downstream output [ 93 ]. Briefly, mammalian sterile 20-like kinase (Mst) activation can be initiated when exposed to diverse stress signals such as extracellular matrix stiffness, mechanic stress, cytoskeletal rearrangement, contact inhibition, and anoxemia [ 94 ]. This signal activation can directly mediate mitochondrial function to affect energy metabolism.…”