title: Lemur tyrosine kinase 2 (LMTK2) is a determinant of cell sensitivity to apoptosis by regulating the levels of the BCL2 family members.
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.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Conti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Majorini
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Fontanella
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mano
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: daniele.lecis@istitutotumori.mi.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000032:analysis; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000032:analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D054645:Protein Phosphatase 1 / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051020:bcl-X Protein / Q000032:analysis*
chemical_list: C494811:BCL2L1 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D066246:ErbB Receptors; D000071679:Glycogen Synthase Kinase 3 beta; C470798:LMTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054645:Protein Phosphatase 1
keywords: Apoptosis regulation; Cancer cell death; Cytotoxic compounds; LMTK2; TRAIL