Fig. 1
From: Biological function of Lemur tyrosine kinase 2 (LMTK2): implications in neurodegeneration
Potential LMTK2-related neurodegenerative mechanisms in Alzheimer’s disease. In healthy cells, CDK5/p35 phosphorylates and activates LMTK2. Activated LMTK2 inactivates PP1C by phosphorylating it which leads to increased inhibitory phosphorylation of GSK3β. In physiological conditions, (A) CDK5/p35 and GSK3β phosphorylates tau. (B) GSK3β also phosphorylates KLC2 to regulate kinesin-1 based transport while (C) PP1C inhibits pro-apoptotic factor Bim. Alzheimer’s disease related neuronal stress (e.g. β-amyloid, ROS etc.) induces calpain mediated cleavage of the CDK5 activator subunit p35 into p25 and p10. p25 prolongs CDK5 activity. Whether CDK5/p25 can activate LMTK2 in the same way as CDK5/p35 is not known. This and neuronal stress related reduced LMTK2 expression lead to blocked LMTK2 phosphorylation pathway. Disrupted LMTK2 phosphorylation pathway causes PP1C dephosphorylation and activation which in turn activates GSK3β by removing its inhibitory serine-9 phosphorylation. (A’) Overactivated GSK3β and CDK5/p25 abnormally hyperphosphorylate tau. Abnormal tau hyperphosphorylation disrupts tau function and microtubule network, affects axonal transport, and forms neurofibrillary tangles. (B′) Overactivated GSK3β phosphorylates KLC2 resulting in cargo release and disrupted Smad2 transport, and signalling. (C′) Overactivated GSK3β supresses anti-apoptotic Bcl-2 and increases the pro-apoptotic Bim levels, and signalling. Activated PP1 inhibits Bim however, it cannot counterbalance GSK3β mediated Bim activation and apoptosis. [Colour codes: Green symbols are functionally active, red symbols are inactive enzymes. Note that thickness of arrows and colour shades reflect activity levels where thin arrows/light colours represent low activity, and thick arrows/dark colours high activity. Abbreviations: Bcl-2 = B-cell lymphoma-2; Bim = Bcl-2-interacting mediator of cell death; CDK5 = cyclin-dependent kinase-5; GSK3β = glycogen synthase kinase-3β; KLC2 = kinesin-1 light chain 2; LMTK2 = lemur tyrosine kinase 2; PP1C = catalytic subunit of protein phosphatase-1; ROS = reactive oxygen species]