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dc.contributor.authorManser, C
dc.contributor.authorGuillot, F
dc.contributor.authorVagnoni, A
dc.contributor.authorDavies, J
dc.contributor.authorLau, K-F
dc.contributor.authorMcLoughlin, D M
dc.contributor.authorDe Vos, K J
dc.contributor.authorMiller, C C J
dc.date.accessioned2012-09-17T08:48:38Z
dc.date.available2012-09-17T08:48:38Z
dc.date.issued2012-05-31
dc.identifier.citationLemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo. 2012, 31 (22):2773-82 Oncogeneen_GB
dc.identifier.issn1476-5594
dc.identifier.pmid21996745
dc.identifier.doi10.1038/onc.2011.437
dc.identifier.urihttp://hdl.handle.net/10147/244217
dc.description.abstractA recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3β (GSK3β). KLC2 phosphorylation by GSK3β induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3β on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-β (TGFβ) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFβ-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.
dc.language.isoenen
dc.rightsArchived with thanks to Oncogeneen_GB
dc.subject.meshBlotting, Western
dc.subject.meshCell Nucleus
dc.subject.meshCell Proliferation
dc.subject.meshFluorescent Antibody Technique
dc.subject.meshGlycogen Synthase Kinase 3
dc.subject.meshHeLa Cells
dc.subject.meshHumans
dc.subject.meshImmunoenzyme Techniques
dc.subject.meshImmunoprecipitation
dc.subject.meshMembrane Proteins
dc.subject.meshMicrotubule-Associated Proteins
dc.subject.meshPhosphorylation
dc.subject.meshProtein Phosphatase 1
dc.subject.meshProtein-Serine-Threonine Kinases
dc.subject.meshRNA, Messenger
dc.subject.meshRNA, Small Interfering
dc.subject.meshReal-Time Polymerase Chain Reaction
dc.subject.meshReceptors, Transforming Growth Factor beta
dc.subject.meshSignal Transduction
dc.subject.meshSmad2 Protein
dc.subject.meshTransforming Growth Factor beta
dc.subject.meshTwo-Hybrid System Techniques
dc.titleLemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Neuroscience P037, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.en_GB
dc.identifier.journalOncogeneen_GB
dc.description.provinceLeinsteren
html.description.abstractA recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3β (GSK3β). KLC2 phosphorylation by GSK3β induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3β on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-β (TGFβ) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFβ-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.


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