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YES oncogenic activity is specified by its SH4 domain and regulates RAS/MAPK signaling in colon carcinoma cells

Fanny Dubois1, Cédric Leroy2, Valérie Simon3

  • 1CNRS UMR5237, University of Montpellier, CRBM 1919 Route de Mende, 34000 Montpellier, France ; CNRS, UMR5203 CNRS, INSERM U661 University of Montpellier, IGF 34000 Montpellier, France.

American Journal of Cancer Research
|August 14, 2015
PubMed

Insights

The SRC family kinase YES, through SH4 domain palmitoylation, drives colorectal cancer progression by activating RAS/MAPK signaling. This mechanism is distinct from SRC, highlighting YES

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Members of the SRC family of tyrosine kinases (SFS) play crucial roles in human cancers, but their specific involvement in tumorigenesis is not fully understood.
  • Previous research indicated that YES kinase regulates unique oncogenic signaling pathways critical for colorectal cancer (CRC) progression, distinct from SRC.
  • The precise molecular mechanisms underlying YES's oncogenic role in CRC require further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which YES kinase promotes colorectal cancer progression.
  • To determine the role of the SH4 domain and palmitoylation in YES kinase's oncogenic activity.
  • To identify the specific downstream signaling pathways regulated by YES in colorectal cancer cells.

Main Methods:

  • Site-directed mutagenesis to delete or add palmitoylation sites in the SH4 domain of YES and SRC kinases.
  • SILAC (Stable Isotope Labeling by Amino acid in Cell culture) phosphoproteomic analysis to identify YES kinase substrates.
  • Western blotting and functional assays to assess signaling pathway activation (e.g., RAS/MAPK) and cell transformation.

Main Results:

  • YES oncogenic signaling is dependent on palmitoylation of its SH4 domain, which dictates its localization to cholesterol-enriched membrane micro-domains.
  • Deletion of the palmitoylation site abolished YES's transforming activity, while its addition to SRC conferred transforming properties.
  • YES primarily phosphorylates micro-domain-associated cell adhesion molecules, receptor tyrosine kinases (e.g., EGFR), and upstream regulators of RAS/MAPK signaling (SHC, SHP2).
  • SRC lacks palmitoylation and does not target these specific substrates.
  • YES down-regulation attenuated EGFR-induced MAPK activity, and increased RAS activity rescued cell transformation lost upon YES silencing.

Conclusions:

  • The SH4 domain and its palmitoylation are critical determinants of SRC family kinase oncogenic activity specificity.
  • YES kinase selectively induces RAS/MAPK signaling in colorectal cancer cells through palmitoylation-dependent mechanisms.
  • Targeting YES-mediated signaling pathways represents a potential therapeutic strategy for colorectal cancer.
Keywords:
SRCYEScolon canceroncogenic signalingphosphoproteomicstyrosine kinase

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