Myosin VI and its interacting protein LMTK2 regulate tubule formation and transport to the endocytic recycling compartment
JOURNAL OF CELL SCIENCE
Authors: Chibalina, Margarita V.; Seaman, Matthew N. J.; Miller, Christopher C.; Kendrick-Jones, John; Buss, Folma
Abstract
Myosin VI is an actin-based retrograde motor protein that plays a crucial role in both endocytic and secretory membrane trafficking pathways. Myosin VI's targeting to and function in these intracellular pathways is mediated by a number of specific binding partners. In this paper we have identified a new myosin-VI-binding partner, lemur tyrosine kinase 2 (LMTK2), which is the first transmembrane protein and kinase that directly binds to myosin VI. LMTK2 binds to the WWY site in the C-terminal myosin VI tail, the same site as the endocytic adaptor protein Dab2. When either myosin VI or LMTK2 is depleted by siRNAs, the transferrin receptor (TfR) is trapped in swollen endosomes and tubule formation in the endocytic recycling pathway is dramatically reduced, showing that both proteins are required for the transport of cargo, such as the TfR, from early endosomes to the endocytic recycling compartment.
Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo
ONCOGENE
Authors: Manser, C.; Guillot, F.; Vagnoni, A.; Davies, J.; Lau, K-F; McLoughlin, D. M.; De Vos, K. J.; Miller, C. C. J.
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-3 beta (GSK3b). KLC2 phosphorylation by GSK3 beta induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3 beta 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-beta (TGF beta) 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 TGF beta-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling. Oncogene (2012) 31, 2773-2782; doi: 10.1038/onc.2011.437; published online 26 September 2011
COA
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