Abstract
The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis. Recently, multiple studies have identified a wide range of upstream regulators of the Hippo pathway, including mechanical cues and ligands of G protein-coupled receptors (GPCRs). Through the activation related G proteins and possibly rearrangements of actin cytoskeleton, GPCR signaling can potently modulate the phosphorylation states and activity of YAP and TAZ, two homologous oncogenic transcriptional co-activators, and major effectors of the Hippo pathway. Herein, we summarize the network, regulation, and functions of GPCR-Hippo signaling, and we will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.
Highlights
Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis
High Yes-association protein (YAP)/TAZ expression in cancer may predict resistance to therapies and cancer relapse [69,70]. These results demonstrate that Hippo pathway, especially YAP/TAZ activity, is involved in human cancer development and may function as a molecular target for cancer diagnosis and therapy
Adhesion G protein-coupled receptors (GPCRs) link cells to their neighbors and probably cell matrix [88], these receptors may link physical signals to the Representative GPCRs that are most frequently implicated in human cancer are shown and their regulation on YAP/TAZ activation are listed in the following table
Summary
The Hippo pathway is initially established in Drosophila melanogaster (fruit flies), following extensive genetic screens for tumor suppressors, and is highly conserved in mammals [1,2]. The core Hippo pathway in mammals can be represented by a kinase cascade consisting of Ste20-like kinases 1/2 (MST1/2), MAP kinase kinase kinase kinases (MAP4K1-7), Large tumor suppressor 1/2 (LATS1/2), Salvador 1 (SAV1, known as WW45), MOB kinase activator 1A/B (MOB1A/B), Yes-association protein (YAP), and Transcriptional coactivator with PDZ-binding motif (TAZ, known as WWTR1), TEA domain family members (TEAD1-4), and Vestigial-like family member 4 (VGLL4). Ras association domain family (RASSF) proteins interact with MST1/2 or SAV1, and may mediate RAS signaling to the Hippo pathway [19,20,21]. Cell-cell contact is well-known to suppress YAP/TAZ activity by promoting LATS1/2 activation [7] The mechanical force, such as stiffness of extracellular matrix (ECM), cell geometry and shear stress, regulates phosphorylation and subcellular localization of YAP/TAZ, and recently small GTPase RAP2 has been shown to mediate matrix stiffness signals to LATS1/2 [22,23]. G protein-coupled receptors (GPCRs) can mediate diverse diffusive signals to modulate Hippo pathway activity, the regulation of the Hippo pathway by GPCR signaling will be further discussed below [30,31,32]
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