Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.

Hdl Handle:
http://hdl.handle.net/10147/244217
Title:
Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.
Authors:
Manser, C; Guillot, F; Vagnoni, A; Davies, J; Lau, K-F; McLoughlin, D M; De Vos, K J; Miller, C C J
Affiliation:
Department of Neuroscience P037, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
Citation:
Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo. 2012, 31 (22):2773-82 Oncogene
Journal:
Oncogene
Issue Date:
31-May-2012
URI:
http://hdl.handle.net/10147/244217
DOI:
10.1038/onc.2011.437
PubMed ID:
21996745
Abstract:
A 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.
Item Type:
Article
Language:
en
MeSH:
Blotting, Western; Cell Nucleus; Cell Proliferation; Fluorescent Antibody Technique; Glycogen Synthase Kinase 3; HeLa Cells; Humans; Immunoenzyme Techniques; Immunoprecipitation; Membrane Proteins; Microtubule-Associated Proteins; Phosphorylation; Protein Phosphatase 1; Protein-Serine-Threonine Kinases; RNA, Messenger; RNA, Small Interfering; Real-Time Polymerase Chain Reaction; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Two-Hybrid System Techniques
ISSN:
1476-5594

Full metadata record

DC FieldValue Language
dc.contributor.authorManser, Cen_GB
dc.contributor.authorGuillot, Fen_GB
dc.contributor.authorVagnoni, Aen_GB
dc.contributor.authorDavies, Jen_GB
dc.contributor.authorLau, K-Fen_GB
dc.contributor.authorMcLoughlin, D Men_GB
dc.contributor.authorDe Vos, K Jen_GB
dc.contributor.authorMiller, C C Jen_GB
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.en_GB
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

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