Cleavage of doublecortin-like kinase by calpain releases an active kinase fragment from a microtubule anchorage domain.
Doublecortin-like kinase (DCLK) is widely expressed in postmitotic neurons throughout the embryonic nervous system. DCLK consists of an N-terminal doublecortin domain, responsible for its localization to microtubules, and a C-terminal serine-threonine kinase domain. Here we report that DCLK is a physiological substrate for the cysteine protease calpain. Cleavage of DCLK by calpain severs the kinase domain from its microtubule anchorage domain and releases it into the cytoplasm. The isolated kinase domain retains catalytic activity and is structurally similar to CPG16, a second product of the DCLK gene expressed in the adult brain that lacks the doublecortin domain. We propose that in neurons cleavage of DCLK by calpain represents a calcium responsive mechanism to regulate localization of the DCLK kinase domain.
Burgess
H A
HA
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Reiner
O
O
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D003600:Cytosol / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D000089742:Doublecortin-Like Kinases; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000201:enzymology*; D008957:Models, Genetic; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection
D004151:Dipeptides; D000089622:Doublecortin Domain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C071482:calpeptin; D005982:Glutathione Transferase; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002154:Calpain