TY  - JOUR
AU  - Wesener, Marie C
AU  - Weiler, Sofia M E
AU  - Bissinger, Michaela
AU  - Klessinger, Tobias F
AU  - Rose, Fabian
AU  - Merker, Sabine
AU  - Luzarowski, Marcin
AU  - Ruppert, Thomas
AU  - Helm, Barbara
AU  - Klingmüller, Ursula
AU  - Schirmacher, Peter
AU  - Breuhahn, Kai
TI  - CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer.
JO  - International journal of molecular sciences
VL  - 25
IS  - 15
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2024-01643
SP  - 8549
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Liver Neoplasms: metabolism
KW  - Liver Neoplasms: pathology
KW  - Liver Neoplasms: genetics
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Transcription Factors: metabolism
KW  - Transcription Factors: genetics
KW  - YAP-Signaling Proteins: metabolism
KW  - Carcinoma, Hepatocellular: metabolism
KW  - Carcinoma, Hepatocellular: pathology
KW  - Carcinoma, Hepatocellular: genetics
KW  - Nuclear Proteins: metabolism
KW  - Nuclear Proteins: genetics
KW  - Proto-Oncogene Mas
KW  - Cell Line, Tumor
KW  - Protein Binding
KW  - MAP Kinase Signaling System
KW  - Gene Expression Regulation, Neoplastic
KW  - Signal Transduction
KW  - AP1 (Other)
KW  - BioID (Other)
KW  - CRK (Other)
KW  - HCC (Other)
KW  - Hippo (Other)
KW  - MS (Other)
KW  - TEAD (Other)
KW  - c-Jun (Other)
KW  - proteomics (Other)
KW  - survival (Other)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - CRKL protein (NLM Chemicals)
KW  - YAP-Signaling Proteins (NLM Chemicals)
KW  - MAS1 protein, human (NLM Chemicals)
KW  - YAP1 protein, human (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Proto-Oncogene Mas (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39126118
C2  - pmc:PMC11312940
DO  - DOI:10.3390/ijms25158549
UR  - https://inrepo02.dkfz.de/record/292155
ER  -