Alternative titles; symbols
HGNC Approved Gene Symbol: DCLK2
Cytogenetic location: 4q31.23-q31.3 Genomic coordinates (GRCh38): 4:150,078,445-150,257,438 (from NCBI)
Edelman et al. (2005) cloned rat Dclk2, which they called Dck2. The deduced protein contains an N-terminal doublecortin (DCX; 300121) domain, followed by a serine-, threonine-, and proline-rich region and a C-terminal kinase domain. Northern blot analysis revealed that expression of Dck2 increased in mouse brain during the second half of embryonic development and remained high in adult brain. Immunofluorescence confocal microscopy showed that Dck2 localized to both axons and dendrites of cultured rat sympathetic neurons.
By searching for mouse genes encoding a CAMK (see 604998)-type kinase domain, Ohmae et al. (2006) cloned 3 splice variants of Dclk2, which they called Cl2-alpha, Cl2-beta-1, and Cl2-beta-2. The deduced Cl2-alpha and Cl2-beta-2 proteins contain 771 and 714 amino acids, respectively, and differ only at their C termini. Cl2-beta-1 contains an additional glutamine relative to Cl2-beta-2. Northern blot analysis showed high Cl2 expression in mouse brain and little to no expression in other tissues examined. In situ hybridization revealed Cl2 expression in neurons, but not in glial cells, in most adult mouse forebrain areas. Cl2 was also detected in the hippocampal CA1 pyramidal cell layer. Mouse Cl2 colocalized with microtubules in transfected HeLa cells.
Edelman et al. (2005) found that purified rat Dck2 bound and stabilized rat brain microtubules in vitro, and that epitope-tagged rat Dck2 bound to newly polymerized microtubules in transfected COS cells. Mutation analysis revealed that the DCX domain of Dck2 was required for microtubule binding. Using a synthetic peptide, Edelman et al. (2005) showed that the C-terminal kinase domain of rat Dck2 functioned as a protein kinase independent of the DCX domain. Dck2 exhibited autophosphorylation, and phosphorylation of Dck2 reduced its affinity for microtubules. When overexpressed in COS cells or rat sympathetic neurons, Dck2 colocalized with microtubules, resulting in microtubule bundling and stabilization against cold-induced depolymerization.
Ohmae et al. (2006) found that mouse Cl2 had significant kinase activity in the absence of calcium and that it lacked significant calmodulin (see 114180)-binding activity. In transfected COS-7 cells, Cl2 suppressed cAMP-activated CRE (see CREB1; 123810)-dependent gene expression. Downregulation of CRE-dependent gene activation was mediated by phosphorylated Torc2 (CRTC2; 608972) and retention of Torc2 in the cytoplasm. Overexpression of Cl2 also induced microtubule bundling in transfected HeLa cells and induced the development of aberrant multinucleated cells.
By genomic sequence analysis, Edelman et al. (2005) mapped the DCLK2 gene to chromosome 4q31.23.
Ohmae et al. (2006) mapped the mouse Dclk2 gene to chromosome 3F1.
Kerjan et al. (2009) found that heterozygous and homozygous Dclk2-null mice were viable and fertile, had normal brain morphology, and no compensatory changes in expression of either Dcx or Dclk1 (604742). However, double-mutant Dcx/Dclk2-null mice showed poor survival, with only about 10% alive past 5 months of age. In addition, Dcx/Dclk2-null mice showed spontaneous seizures, often associated with behavioral arrest and forelimb myoclonus. These seizures were noted to start at about 3 weeks of age. EEG studies were consistent with a hippocampal focus. Histologic studies showed compounded dyslamination of the hippocampus, with a discontinuous CA1 field, neuronal displacement, and reduced packing density of the dentate granule neuron layer, resulting in increased thickness. The neocortex appeared to have normal organization. Dcx/Dclk2-null mice had reduced GABA inhibition secondary to overall network disorganization, as well as a decrease in dendritic arbors, which suggested an in insufficient receptive field for inhibitory input. In situ hybridization studies in normal mice showed coexpression of Dcx and Dclk2 in the hippocampus during embryonic and postnatal stages. Comparative studies in other mutant mice suggested that the Dcx deficiency was the major contributor to lamination defects, and that Dcx and Dclk2 are functionally redundant. Kerjan et al. (2009) concluded that this mutant mouse model shows similarities to human X-linked lissencephaly (LISX1; 300067).
Edelman, A. M., Kim, W.-Y., Higgins, D., Goldstein, E. G., Oberdoerster, M., Sigurdson, W. Doublecortin kinase-2, a novel doublecortin-related protein kinase associated with terminal segments of axons and dendrites. J. Biol. Chem. 280: 8531-8543, 2005. [PubMed: 15611072] [Full Text: https://doi.org/10.1074/jbc.M411027200]
Kerjan, G., Koizumi, H., Han, E. B., Dube, C. M., Djakovic, S. N., Patrick, G. N., Baram, T. Z., Heinemann, S. F., Gleeson, J. G. Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures. Proc. Nat. Acad. Sci. 106: 6766-6771, 2009. [PubMed: 19342486] [Full Text: https://doi.org/10.1073/pnas.0812687106]
Ohmae, S., Takemoto-Kimura, S., Okamura, M., Adachi-Morishima, A., Nonaka, M., Fuse, T., Kida, S., Tanji, M., Furuyashiki, T., Arakawa, Y., Narumiya, S., Okuno, H., Bito, H. Molecular identification and characterization of a family of kinases with homology to Ca(2+)/calmodulin-dependent protein kinases I/IV. J. Biol. Chem. 281: 20427-20439, 2006. [PubMed: 16684769] [Full Text: https://doi.org/10.1074/jbc.M513212200]