YAP1

Overview

YAP1 (Yes-associated protein 1) is a transcriptional co-activator and downstream effector of the Hippo signaling pathway. In gastric cancer, YAP1 signaling is perturbed by oncogenic RHOA mutations, linking Rho GTPase biology to Hippo pathway dysregulation in diffuse-type gastric adenocarcinoma.

Alterations observed in the corpus

  • YAP1 signaling is perturbed by a germline RHOA p.R129W variant identified in a Korean HDGC-like family: the variant showed elevated GTP-binding and altered YAP1 signaling in functional assays. PMID:24816255
  • RHOA-activated diffuse gastric tumors may be susceptible to Rho/ROCK or YAP1-pathway inhibitors (preclinical hypothesis; no clinical trial data reported). PMID:24816255
  • Mechanotransducer in gallbladder cancer-associated fibroblasts; nuclear translocation driven by stiff matrix (16 kPa); required for stiffness-induced SEMA7A transcription; YAP1 shRNA or verteporfin abolishes GF activation and SEMA7A secretion. PMID:24997986
  • Co-amplified with BIRC2 at 11q22 in HPV(-) HNSCC (TCGA, n=279); majority of 11q13-amplified tumours carried large telomeric 11q22 deletions including ATM and CASP1-5-12; inferred selection via BIRC2-FADD-caspase cascade inhibiting cell death PMID:25631445
  • Focal amplification in 1–3 desmoplastic melanoma tumours; IHC confirmed protein-level overexpression PMID:26343386
  • YAP1 is not mutated but accumulates in nuclei of NF2-loss uRCC tumours (26% of cohort); shRNA knockdown of YAP1 in NF2-loss nccRCC lines ACHN and LB996-RCC reduces S- and G2/M-phase cells (P<0.001) and decreases soft-agar colony formation, validating functional dependency. PMID:27713405
  • Focally amplified (3%) in UPS/MFS and also amplified in 16% of DDLPS as an adipocyte-differentiation inhibitor; the YAP1/VGLL3 TEAD-cofactor target signature is strongly expressed (p=1e-24) in UPS/MFS, supporting a role for Hippo pathway activation in these sarcoma subtypes PMID:29100075.

Cancer types (linked)

  • STAD – YAP1 is a downstream effector of RHOA signaling in diffuse-type gastric adenocarcinoma; RHOA variants disrupt YAP1 signaling and are proposed as a therapeutic vulnerability. PMID:24816255

Co-occurrence and mutual exclusivity

  • YAP1 pathway alteration is linked to RHOA gain-of-function in diffuse gastric carcinoma and HDGC-like familial gastric cancer. PMID:24816255

Therapeutic relevance

  • Rho/ROCK or YAP1-pathway inhibitors are proposed as candidate therapies for RHOA-activated diffuse gastric tumors; this remains a preclinical hypothesis with no clinical validation yet. PMID:24816255

Open questions

  • Whether YAP1 pathway inhibition can be clinically translated into effective therapy for RHOA-mutant diffuse gastric cancer has not been tested prospectively.

Sources

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