Regulation of Kinesin: Implications for Neuronal Development

Abstract

Rapid organelle transport is required for process growth and establishment of specialized structures during neuronal development. Furthermore, maintenance of mature neuronal architecture and function depends on the proper delivery of materials to specialized domains within axons, such as nodes of Ranvier and synaptic terminals. Kinesin is the most abundant member of the kinesin superfamily of microtubule-based motors. Kinesins are responsible for anterograde transport of an assortment of membrane-bound organelles in all cell types. Kinesin is enriched in neurons, but relatively little is known about the developmental regulation of its expression, localization, and function in nervous tissue. By examining kinesin expression in developing brain and in cultures of cortical neurons, we found that kinesin is enriched in elongating neurites, including their growing tips, the growth cones. To gain understanding of mechanisms that underlie the delivery of proteins to specific cellular subcompartments, we focused on studying modifications on kinesin that lead to its dissociation from membranes. Since kinesin is a phosphoprotein in vivo, we evaluated the correlation between kinesin phosphorylation and its membrane association and identified a number of kinases which phosphorylate kinesin and alter its function.

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

“…Phosphorylation of kinesin-1 by various kinases can regulate its activities and affect anterograde FAT (22,24,28). Previous studies on phosphorylation of KLC at the 63-90 epitope suggest that this site regulates binding of kinesin-1 to vesicle cargoes (23,40).…”

“…The ability of nanomolar levels of oA␤ to inhibit FAT suggested that the molecular mechanism of inhibition is likely to be enzymatic (24) rather than a physical blockade. Abnormal phosphorylation of different neuronal cytoskeletal proteins is a characteristic hallmark in AD and our previous studies in isolated axoplasm have identified multiple kinase and phosphatase activities that can inhibit FAT (22,24,26,28). A number of different phosphotransferase activities are altered in brains of AD patients, AD animal models, and cell lines exposed to A␤.…”

“…The list of abnormal kinase activities in AD is extensive, among them several unrelated serine/threonine protein kinases including GSK3 (23,29,30), p38 (31), JNK (31), cdk5 (32,33), and CK2 (34). Interestingly, many of these enzymes are involved in regulation of FAT (28,29).…”

“…CK2 is another kinase that can inhibit both anterograde and retrograde FAT (28). Based on results showing that heterogeneous A␤ could directly stimulate CK2 kinase activity in vitro (35), the role of endogenous CK2 activation in oA␤-induced FAT inhibition was evaluated.…”

“…Pathogenic forms of Huntingtin and androgen receptor (24,25) as well as tau filaments (40) and mutant presenilin 1 (23), all inhibit FAT by activation of a kinase or phosphatase. A variety of kinases have been found to affect FAT in axoplasm (28), and multiple kinase activities are elevated in AD (GSK, JNK, CK2). These provide candidate kinase activities that might be elevated by oA␤.…”