Ablation of Dicer leads to widespread perturbation of signaling pathways

Nandini A. Sahasrabuddhe, Tai Chung Huang, Praveen Kumar, Yi Yang, Bidyut Ghosh, Steven D. Leach, Raghothama Chaerkady, Akhilesh Pandey

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Dicer is an essential ribonuclease involved in the biogenesis of miRNAs. Previous studies have reported downregulation of Dicer in multiple cancers including hepatocellular carcinoma. To identify signaling pathways that are altered upon Dicer depletion, we carried out quantitative phosphotyrosine profiling of liver tissue from Dicer knockout mice. We employed antibody-based enrichment of phosphotyrosine containing peptides coupled with SILAC spike-in approach for quantitation. High resolution mass spectrometry-based analysis identified 349 phosphotyrosine peptides corresponding to 306 unique phosphosites of which 75 were hyperphosphorylated and 78 were hypophosphorylated. Several receptor tyrosine kinases including MET, PDGF receptor alpha, Insulin-like growth factor 1 and Insulin receptor as well as non-receptor tyrosine kinases such as Src family kinases were found to be hyperphosphorylated upon depletion of Dicer. In addition, signaling molecules such as IRS-2 and STAT3 were hyperphosphorylated. Activation of these signaling pathways has been implicated previously in various types of cancers. Interestingly, we observed hypophosphorylation of molecules including focal adhesion kinase and paxillin. Our study profiles the perturbed signaling pathways in response to dysregulated miRNAs resulting from depletion of Dicer. Our findings warrant further studies to investigate oncogenic effects of downregulation of Dicer in cancers.

Original languageEnglish (US)
Pages (from-to)389-394
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume463
Issue number3
DOIs
StatePublished - Jun 14 2015

Keywords

  • Dicer
  • Pathways
  • Phosphotyrosine
  • Receptor tyrosine kinase
  • SILAC

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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