Molecule Information

General Information of the Molecule (ID: Mol04172)

• Name: Yes-associated protein 1 (YAP1) ,Homo sapiens
• Synonyms: Protein yorkie homolog; Yes-associated protein YAP65 homolog
• Molecule Type: Protein
• Gene Name: YAP1
• Gene ID: 10413
• Location: chr11:102110447-102233424[+]
• Sequence:
  MDPGQQPPPQPAPQGQGQPPSQPPQGQGPPSGPGQPAPAATQAAPQAPPAGHQIVHVRGD
  SETDLEALFNAVMNPKTANVPQTVPMRLRKLPDSFFKPPEPKSHSRQASTDAGTAGALTP
  QHVRAHSSPASLQLGAVSPGTLTPTGVVSGPAATPTAQHLRQSSFEIPDDVPLPAGWEMA
  KTSSGQRYFLNHIDQTTTWQDPRKAMLSQMNVTAPTSPPVQQNMMNSASGPLPDGWEQAM
  TQDGEIYYINHKNKTTSWLDPRLDPRFAMNQRISQSAPVKQPPPLAPQSPQGGVMGGSNS
  NQQQQMRLQQLQMEKERLRLKQQELLRQAMRNINPSTANSPKCQELALRSQLPTLEQDGG
  TQNPVSSPGMSQELRTMTTNSSDPFLNSGTYHSRDESTDSGLSMSSYSVPRTPDDFLNSV
  DEMDTGDTINQSTLPSQQNRFPDYLEAIPGTNVDLGTLEGDGMNIEGEELMPSLQEALSS
  DILNDMESVLAATKLDKESFLTWL
• 3D-structure: PDB ID: 3KYS; Classification: Transcription/protein binding; Method: X-ray diffraction; Resolution: 2.80 Å
• Function: Transcriptional regulator with dual roles as a coactivator and corepressor. Critical downstream regulatory target in the Hippo signaling pathway, crucial for organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The Hippo signaling pathway core involves a kinase cascade featuring STK3/MST2 and STK4/MST1, along with its regulatory partner SAV1, which phosphorylates and activates LATS1/2 in complex with their regulatory protein, MOB1. This activation leads to the phosphorylation and inactivation of the YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Phosphorylation of YAP1 by LATS1/2 prevents its nuclear translocation, thereby regulating the expression of its target genes (PubMed:18158288, PubMed:26598551, PubMed:34404733). The transcriptional regulation of gene expression requires TEAD transcription factors and modulates cell growth, anchorage-independent growth, and induction of epithelial- mesenchymal transition (EMT) (PubMed:18579750). Plays a key role in tissue tension and 3D tissue shape by regulating the cortical actomyosin network, acting via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). It also suppresses ciliogenesis by acting as a transcriptional corepressor of TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, regulates TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). Synergizes with WBP2 to enhance PGR activity (PubMed:16772533). .; [Isoform 2]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). .; [Isoform 3]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). .
• Uniprot ID: YAP1_HUMAN
• Ensembl ID: ENSG00000137693
• HGNC ID: HGNC:16262

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Eflornithine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Osteosarcoma [ICD-11: 2B51.0] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Eflornithine
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: 6-8-week-old female nude mice, with osteosarcoma cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839.

References

• Ref 1: Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma. Cell Oncol (Dordr). 2024 Oct;47(5):1845-1861.