CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Liver Neoplasms*/metabolism ; Liver Neoplasms*/pathology ; Liver Neoplasms*/genetics ; Adaptor Proteins, Signal Transducing*/metabolism ; Adaptor Proteins, Signal Transducing*/genetics ; Transcription Factors*/metabolism ; Transcription Factors*/genetics ; YAP-Signaling Proteins*/metabolism ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/genetics ; Nuclear Proteins*/metabolism ; Nuclear Proteins*/genetics; Humans ; Proto-Oncogene Mas ; Cell Line, Tumor ; Protein Binding ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Signal Transduction
    • Abstract:
      The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.
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    • Grant Information:
      314905040 Deutsche Forschungsgemeinschaft SFB/TR 209 "Liver Cancer"
    • Contributed Indexing:
      Keywords: AP1; BioID; CRK; HCC; Hippo; MS; TEAD; c-Jun; proteomics; survival
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Transcription Factors)
      0 (CRKL protein)
      0 (YAP-Signaling Proteins)
      0 (MAS1 protein, human)
      0 (YAP1 protein, human)
      0 (Nuclear Proteins)
      0 (Proto-Oncogene Mas)
    • Publication Date:
      Date Created: 20240810 Date Completed: 20240810 Latest Revision: 20240919
    • Publication Date:
      20240920
    • Accession Number:
      PMC11312940
    • Accession Number:
      10.3390/ijms25158549
    • Accession Number:
      39126118