Properties, regulation, and in vivo functions of a novel protein kinase D

Caenorhabditis elegans DKF-2 links diacylglycerol second messenger to the regulation of stress responses and life span

Hui Feng, Min Ren, Lu Chen, Charles S. Rubin

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Protein kinase D (PKD) isoforms are protein kinase C effectors in signaling cascades controlled by diacylglycerol (DAG). All PKDs are regulated by DAG/phorbol 12-myristate 13-acetate-binding C1 domains and an activation loop (A-loop). To understand how PKD isoforms diversify DAG signaling networks, it is essential to determine redundant and novel properties of their regulatory domains, characterize factors controlling PKD gene expression, and discover their in vivo physiological roles. Studies on a novel PKD, Caenorhabditis elegans DKF-2 (D kinase family-2), addressed these topics. The C1b domain mediates phorbol 12-myristate 13-acetate-induced translocation and activation of DKF-2. However, when DAG is elevated, C1a and C1b contribute equally to targeting/activation of DKF-2. DKF-2 C1 domains do not inhibit catalytic activity; they mediate delivery of DKF-2 to a membrane where protein kinase C phosphorylates Ser925 and Ser929 in the A-loop. This potently stimulates DKF-2 catalytic activity. Phosphorylation of Ser 925 alone switches on 70% of maximal kinase activity. Persistent phosphorylation of Ser929 tags DKF-2 for proteasomal degradation; Ser(P)925 plays a minor role in DKF-2 degradation. GATA enhancer sequences govern DKF-2 expression in intestine in vivo. Adult life span increases 40% in animals lacking DKF-2. In thermally stressed wild type animals, the DAF-16 transcription factor is segregated from the nuclei of adult intestinal cells. In contrast, DAF-16 enters adult intestinal nuclei of DKF-2-deficient, thermally stressed animals, where it can trigger gene transcription that protects against various insults. The results suggest a mechanism for increased longevity and show that a PKD links DAG signals to regulation of stress responses and life span.

Original languageEnglish (US)
Pages (from-to)31273-31288
Number of pages16
JournalJournal of Biological Chemistry
Volume282
Issue number43
DOIs
StatePublished - Oct 26 2007

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Diglycerides
Caenorhabditis elegans
Second Messenger Systems
Psychological Stress
Phosphotransferases
Chemical activation
Phosphorylation
Animals
Protein Kinase C
protein kinase D
Catalyst activity
Protein Isoforms
Acetates
Degradation
Wild Animals
Transcription
Gene expression
Intestines
Membrane Proteins
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Properties, regulation, and in vivo functions of a novel protein kinase D : Caenorhabditis elegans DKF-2 links diacylglycerol second messenger to the regulation of stress responses and life span. / Feng, Hui; Ren, Min; Chen, Lu; Rubin, Charles S.

In: Journal of Biological Chemistry, Vol. 282, No. 43, 26.10.2007, p. 31273-31288.

Research output: Contribution to journalArticle

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abstract = "Protein kinase D (PKD) isoforms are protein kinase C effectors in signaling cascades controlled by diacylglycerol (DAG). All PKDs are regulated by DAG/phorbol 12-myristate 13-acetate-binding C1 domains and an activation loop (A-loop). To understand how PKD isoforms diversify DAG signaling networks, it is essential to determine redundant and novel properties of their regulatory domains, characterize factors controlling PKD gene expression, and discover their in vivo physiological roles. Studies on a novel PKD, Caenorhabditis elegans DKF-2 (D kinase family-2), addressed these topics. The C1b domain mediates phorbol 12-myristate 13-acetate-induced translocation and activation of DKF-2. However, when DAG is elevated, C1a and C1b contribute equally to targeting/activation of DKF-2. DKF-2 C1 domains do not inhibit catalytic activity; they mediate delivery of DKF-2 to a membrane where protein kinase C phosphorylates Ser925 and Ser929 in the A-loop. This potently stimulates DKF-2 catalytic activity. Phosphorylation of Ser 925 alone switches on 70{\%} of maximal kinase activity. Persistent phosphorylation of Ser929 tags DKF-2 for proteasomal degradation; Ser(P)925 plays a minor role in DKF-2 degradation. GATA enhancer sequences govern DKF-2 expression in intestine in vivo. Adult life span increases 40{\%} in animals lacking DKF-2. In thermally stressed wild type animals, the DAF-16 transcription factor is segregated from the nuclei of adult intestinal cells. In contrast, DAF-16 enters adult intestinal nuclei of DKF-2-deficient, thermally stressed animals, where it can trigger gene transcription that protects against various insults. The results suggest a mechanism for increased longevity and show that a PKD links DAG signals to regulation of stress responses and life span.",
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