Abstract
The microtubule (MT)-associated DCX protein plays an essential role in the development of the mammalian cerebral cortex. We report on the identification of a protein kinase, doublecortin kinase-2 (DCK2), with a domain (DC) highly homologous to DCX. DCK2 has MT binding activity associated with its DC domain and protein kinase activity mediated by a kinase domain, organized in a structure in which the two domains are functionally independent. Overexpression of DCK2 stabilizes the MT cytoskeleton against cold-induced depolymerization. Autophosphorylation of DCK2 strongly reduces its affinity for MTs. DCK2 and DCX mRNAs are nervous system-specific and are expressed during the period of cerebrocortical lamination. DCX is down-regulated postnatally, whereas DCK2 persists in abundance into adulthood, suggesting that the DC sequence has previously unrecognized functions in the mature nervous system. In sympathetic neurons, DCK2 is localized to the cell body and to the terminal segments of axons and dendrites. DCK2 may represent a phosphorylation-dependent switch for the reversible control of MT dynamics in the vicinity of neuronal growth cones.
Highlights
Mutations in the doublecortin gene DCX are responsible for cases of X-linked lissencephaly and doublecortex syndrome [1,2,3,4,5,6]
The DC domain of doublecortin kinase-2 (DCK2) is evolutionarily related, nonidentical, with other DC-containing proteins such as DCX, the protein product of the gene mutated in X-lissencephaly/ doublecortex syndrome (Fig. 1, B and C)
Patient mutations have been identified in DCX in amino acids that are highly conserved with the homologous residues within the DC domain of DCK2 (Fig. 1C)
Summary
Mutations in the doublecortin gene DCX are responsible for cases of X-linked lissencephaly and doublecortex syndrome (for which the gene was named) [1,2,3,4,5,6] In these disorders the defective DCX protein fails to perform its normal embryonic function of mediating the migration of neuroblasts from the proliferative ventricular zone toward the pial surface. DCK1 is the only DCK gene described to date in vertebrates, predicted DC domain-kinase fusions are encoded by the genomes of Drosophila and Caenorhabditis elegans. The latter (ZYG-8) has been characterized and shown to be important for mitotic spindle positioning during C. elegans embryogenesis [22]. The patterns of expression, functional activities, regulation, and localization of DCK2 suggest that it functions in parallel to, or in concert with, other members of the DC gene family (DC domain-encoding genes) in events important for neural development and, potentially, in those characteristic of mature nervous systems
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