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

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 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 siRNA 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.

Regulation of Axonal Transport by Protein Kinases

“…Experiments in squid axoplasm suggest that Cdk5 regulates axonal transport indirectly via inhibition of GSK3b (see GSK3b section) [70]. Cdk5 has been shown to activate lemur tyrosine kinase-2 (LMTK2), which in turn phosphorylates and activates protein phosphatase 1 (PP1), thus preventing GSK3b activation [70,73,74]. Cdk5 has also been described to regulate fast retrograde axonal transport through phosphorylation of the dynein adapter protein Ndel1.…”

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

“…Thrombospondin-4 (Thbs4) is also secreted and has known roles in cardiac fibrosis, 22 and its expression increases 25-fold in myofibroblasts with nearly undetectable expression in whole medulla. Insulin-like growth factor binding protein-6 (Igfbp6) is another candidate secreted biomarker, upregulated 4.4-fold and a known target of hedgehog signaling, 45 which is activated in kidney myofibroblasts.…”

“…In the brain, Lmtk2 promotes TGF-b-dependent Smad2 translocation to the nucleus by inactivating GSK3b. 22 Its downregulation during early UUO may therefore reflect a compensatory and adaptive antifibrotic response to chronic injury. Similarly, Thrombospondin-4 (Thbs4) is an extracellular matrix glycoprotein now recognized to induce the endoplasmic reticulum stress response after cardiac injury.…”

The Importance of Tau Phosphorylation for Neurodegenerative Diseases

“…LMTK2 phosphorylates PP1C on T320, thereby inhibiting PP1C activity (159–161). PP1 regulates phosphorylation of GSK3β at the inhibitory phosphorylation site S9 (162, 163), and therefore, via its effect on PP1C, LMTK2 regulates GSK-3β phosphorylation at S9, and ultimately GSK-3 activity (160, 161). Therefore, an alternative strategy for inhibiting GSK-3 activity may be to increase LMTK2 expression or activity.…”