Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.
Affiliation
Department of Neuroscience P037, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.Issue Date
2012-05-31MeSH
Blotting, WesternCell 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
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Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo. 2012, 31 (22):2773-82 OncogeneJournal
OncogeneDOI
10.1038/onc.2011.437PubMed ID
21996745Abstract
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
ArticleLanguage
enISSN
1476-5594ae974a485f413a2113503eed53cd6c53
10.1038/onc.2011.437
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