Characterization of a novel protein kinase D

Caenorhabditis elegans DKF-1 is activated by translocation-phosphorylation and regulates movement and growth in vivo

Hui Feng, Min Ren, Shi Lan Wu, David H. Hall, Charles S. Rubin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Protein kinase D (PKD) isoforms are protein kinase C (PKC) effectors in diacylglycerol (DAG)-regulated signaling pathways. Key physiological processes are placed under DAG control by the distinctive substrate specificity and intracellular distribution of PKDs. Comprehension of the roles of PKDs in homeostasis and signal transduction requires further knowledge of regulatory interplay among PKD and PKC isoforms, analysis of PKC-independent PKD activation, and characterization of functions controlled by PKDs in vivo. Caenorhabditis elegans and mammals share conserved signaling mechanisms, molecules, and pathways Thus, characterization of the C. elegans PKDs could yield insights into regulation and functions that apply to all eukaryotic PKDs. C. elegans DKF-1 (D kinase family-1) contains tandem DAG binding (C1) modules, a PH (pleckstrin homology) domain, and a Ser/Thr protein kinase segment, which are homologous with domains in classical PKDs. DKF-1 and PKDs have similar substrate specificities. Phorbol 12-myristate 13-acetate (PMA) switches on DKF-1 catalytic activity in situ by promoting phosphorylation of a single amino acid Thr588 in the activation loop. DKF-1 phosphorylation and activation are unaffected when PKC activity is eliminated by inhibitors. Both phosphorylation and kinase activity of DKF-1 are extinguished by substituting Ala for Thr588 or Gln for Lys455 ("kinase dead") or incubating with protein phosphatase 2C. Thus, DKF-1 is a PMA-activated, PKC-independent D kinase. In vivo, dkf-1 gene promoter activity is evident in neurons. Both dkf-1 gene disruption (null phenotype) and RNA interference-mediated depletion of DKF-1 protein cause lower body paralysis. Targeted DKF-1 expression corrected this locomotory defect in dkf-1 null animals. Supraphysiological expression of DKF-1 limited C. elegans growth to ∼60% of normal length.

Original languageEnglish (US)
Pages (from-to)17801-17814
Number of pages14
JournalJournal of Biological Chemistry
Volume281
Issue number26
DOIs
StatePublished - Jun 30 2006

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Phosphorylation
Caenorhabditis elegans
Phosphotransferases
Growth
Protein Kinase C
Diglycerides
Chemical activation
Substrate Specificity
protein kinase D
Protein Isoforms
Acetates
Genes
Physiological Phenomena
Signal transduction
Mammals
Phosphoprotein Phosphatases
Substrates
RNA Interference
Paralysis
Protein Kinases

ASJC Scopus subject areas

  • Biochemistry

Cite this

Characterization of a novel protein kinase D : Caenorhabditis elegans DKF-1 is activated by translocation-phosphorylation and regulates movement and growth in vivo. / Feng, Hui; Ren, Min; Wu, Shi Lan; Hall, David H.; Rubin, Charles S.

In: Journal of Biological Chemistry, Vol. 281, No. 26, 30.06.2006, p. 17801-17814.

Research output: Contribution to journalArticle

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abstract = "Protein kinase D (PKD) isoforms are protein kinase C (PKC) effectors in diacylglycerol (DAG)-regulated signaling pathways. Key physiological processes are placed under DAG control by the distinctive substrate specificity and intracellular distribution of PKDs. Comprehension of the roles of PKDs in homeostasis and signal transduction requires further knowledge of regulatory interplay among PKD and PKC isoforms, analysis of PKC-independent PKD activation, and characterization of functions controlled by PKDs in vivo. Caenorhabditis elegans and mammals share conserved signaling mechanisms, molecules, and pathways Thus, characterization of the C. elegans PKDs could yield insights into regulation and functions that apply to all eukaryotic PKDs. C. elegans DKF-1 (D kinase family-1) contains tandem DAG binding (C1) modules, a PH (pleckstrin homology) domain, and a Ser/Thr protein kinase segment, which are homologous with domains in classical PKDs. DKF-1 and PKDs have similar substrate specificities. Phorbol 12-myristate 13-acetate (PMA) switches on DKF-1 catalytic activity in situ by promoting phosphorylation of a single amino acid Thr588 in the activation loop. DKF-1 phosphorylation and activation are unaffected when PKC activity is eliminated by inhibitors. Both phosphorylation and kinase activity of DKF-1 are extinguished by substituting Ala for Thr588 or Gln for Lys455 ({"}kinase dead{"}) or incubating with protein phosphatase 2C. Thus, DKF-1 is a PMA-activated, PKC-independent D kinase. In vivo, dkf-1 gene promoter activity is evident in neurons. Both dkf-1 gene disruption (null phenotype) and RNA interference-mediated depletion of DKF-1 protein cause lower body paralysis. Targeted DKF-1 expression corrected this locomotory defect in dkf-1 null animals. Supraphysiological expression of DKF-1 limited C. elegans growth to ∼60{\%} of normal length.",
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