Lemur tyrosine kinase 2 (LMTK2) is a determinant of cell sensitivity to apoptosis by regulating the levels of the BCL2 family members

Annalisa Conti, Maria Teresa Majorini, Enrico Fontanella, Alberto Bardelli, Mauro Giacca, Domenico Delia, Miguel Mano, Daniele Lecis

Research output: Contribution to journalArticle

Abstract

Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members. In epithelial cells, LMTK2 targeting causes the down-regulation of the BCL2 and BCL-xL anti-apoptotic proteins and the reciprocal up-regulation of the pro-apoptotic protein BIM, while, in cancer cells, LMTK2 knock-down reduces BCL2 without increasing BIM levels. We provide evidence that both BIM and BCL2 proteins are regulated by LMTK2 in a GSK3β- and PP1A-dependent manner and that their perturbation, together with BCL-xL reduction, determines an increased sensitivity not only to TRAIL, but also to other compounds. Overall, our findings suggest a broad function of LMTK2 in the regulation of the apoptotic pathway and highlight LMTK2 as a novel candidate target to increase the cytotoxic activity of chemotherapeutic compounds.

Original languageEnglish
Pages (from-to)59-69
Number of pages11
JournalCancer Letters
Volume389
DOIs
Publication statusPublished - Mar 28 2017

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Keywords

  • Apoptosis regulation
  • Cancer cell death
  • Cytotoxic compounds
  • LMTK2
  • TRAIL

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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