Hippo‐YAP signaling pathway: A new paradigm for cancer therapy

Ma, Yanlei; Yang, Yongzhi; Feng, Wenquan; Wei, Qing; Qin, Huanlong

doi:10.1002/ijc.29073

Cited by 83 publications

(68 citation statements)

References 145 publications

(286 reference statements)

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“…Thymosin β4, a human member of the Actobindin family, has been reported to play the role of both an oncogene and tumor suppressor under different contexts (82,83). SepA shares homology with human MSTs and PAKs, known tumor supressors that are currently being investigated as therapeutic targets (84,85). Human Tenascin-C is reported to play a role in the progression and metastasis of breast cancer and as a potential target (86,87).…”

Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The model organism Dictyostelium discoideum has greatly facilitated our understanding of the signal transduction and cytoskeletal pathways that govern cell motility. Cell-substrate adhesion is downstream of many migratory and chemotaxis signaling events. Dictyostelium cells lacking the tumor suppressor PTEN show strongly impaired migratory activity and adhere strongly to their substrates. We reasoned that other regulators of migration could be obtained through a screen for overly adhesive mutants. A screen of restriction enzyme-mediated integration mutagenized cells yielded numerous mutants with the desired phenotypes, and the insertion sites in 18 of the strains were mapped. These regulators of adhesion and motility mutants have increased adhesion and decreased motility. Characterization of seven strains demonstrated decreased directed migration, flatness, increased filamentous actin-based protrusions, and increased signal transduction network activity. Many of the genes share homology to human genes and demonstrate the diverse array of cellular networks that function in adhesion and migration

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Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Abnormalities in Hippo components occur in many types of human tumors (43). We immunostained liver samples from patients with cHC-CC, ICC, or HCC to detect YAP1 and SMAD2 and observed significant YAP1 activation (greater than grade 2, as defined in Table S1) in 70% of cHC-CCs and 60% of ICCs, but in only 23% of HCCs, 14% of nontumorous cholangiocytes (NT-Chol), and 6% of nontumorous hepatocytes (NT-Hep) (Fig.…”

Section: Yap1 and Tgf-βs-smads In Human Chc-ccs And Iccs And Drugsmentioning

confidence: 99%

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Nishio

Sugimachi

Goto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

160

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Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

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“…Recent evidence indicate that the Gα q and Gα 11 mutations activate the transcriptional coactivator, YAP [163], a critical component of the Hippo signaling pathway that has been extensively studied in controlling tissue homeostasis and organ size [164-166]. The role of aberrant Hippo signaling in cancer development is also under active investigation [167, 168]. GPCRs have been reported to differentially modulate YAP activation.…”

Section: The Similar Pathological Signaling Network Of Viral and Cmentioning

confidence: 99%

Hijacking GPCRs by viral pathogens and tumor

Zhang

Feng

et al. 2016

Biochemical Pharmacology

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G protein-coupled receptors (GPCRs) constitute the largest family of molecules that transduce signal across the plasma membrane. Herpesviruses are successful pathogens that evolved diverse mechanisms to benefit their infection. Several human herpesviruses express GPCRs to exploit cellular signaling cascades during infection. These viral GPCRs demonstrate distinct biochemical and biophysical properties that result in the activation of a broad spectrum of signaling pathways. In immune-deficient individuals, human herpesvirus infection and the expression of their GPCRs are implicated in virus-associated diseases and pathologies. Emerging studies also uncover diverse mutations in components, particularly GPCRs and small G proteins, of GPCR signaling pathways that render the constitutive activation of proliferative and survival signal, which contributes to the oncogenesis of various human cancers. Hijacking GPCR-mediated signaling is a signature shared by diseases associated with constitutively active viral GPCRs and cellular mutations activating GPCR signaling, exposing key molecules that can be targeted for anti-viral and anti-tumor therapy.

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Hippo‐YAP signaling pathway: A new paradigm for cancer therapy

Cited by 83 publications

References 145 publications

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Hijacking GPCRs by viral pathogens and tumor

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