Dissimilar phorbol ester binding properties of the individual cysteine‐rich motifs of protein kinase D

Iglesias, Teresa; Matthews, Sharon A.; Rozengurt, Enrique

doi:10.1016/s0014-5793(98)01189-2

Cited by 59 publications

(77 citation statements)

References 30 publications

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“…DAG binding to PKD is proposed to colocalize PKCs to facilitate Ser-744/Ser-748 phosphorylation, but the role of DAG binding to PKD1 for enzyme activation in lymphocytes has not been fully assessed. Previous studies have shown that PKD-P287G, a PKD1 mutant with a mutated C1b domain that has lost ϳ90% of its DAG/phorbol ester binding capacity, can still be activated in response to antigen receptor triggering (6,29). However, this result does not fully resolve the role of DAG binding for PKD1 activation because PKD-P287G has residual capacity to bind DAG/phorbol esters via its low affinity C1a domain.…”

Section: Resultsmentioning

confidence: 93%

“…The Role of the PKD1 CRD in PKD1 Activation in Lymphocytes-There are two cysteine-rich motifs (C1a and C1b) within the CRD of PKD1 that are required for the enzyme to bind DAG with high affinity and control the intracellular localization of the enzyme (26,29,33). DAG binding to PKD is proposed to colocalize PKCs to facilitate Ser-744/Ser-748 phosphorylation, but the role of DAG binding to PKD1 for enzyme activation in lymphocytes has not been fully assessed.…”

Section: Resultsmentioning

confidence: 99%

“…cDNA Constructs-cDNA constructs encoding wild type PKD1 and various PKD1 mutants in the pcDNA3 mammalian expression vector have been described previously: PKD1 wild type, PKD⌬PH, PKD-S744A/S748A, PKD-S744E/S748E, and PKD-P155G/P287G (15,19,28,29). cDNA constructs encoding a chimeric fusion protein between green fluorescent protein (GFP) and the above PKD1 mutants were generated by subcloning an EcoRI cDNA fragment encoding the PKD1 constructs into the EcoRI site of pEF-plink2-GFP C3 (7) to generate a GFP-PKD expression vector.…”

Section: Methodsmentioning

confidence: 99%

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Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Wood

Marklund

Cantrell

2005

Journal of Biological Chemistry

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The serine/threonine kinase protein kinase D1 (PKD1) is a protein kinase C (PKC) substrate that mediates antigen receptor signal transduction in lymphocytes. PKC phosphorylates serines 744/748 within the PKD1 catalytic domain, and this is proposed to be necessary and sufficient for enzyme activation. Hence, a PKD1 mutant with alanine substituted at positions 744 and 748 (PKD-S744A/S748A) is catalytically inactive. Conversely, a PKD1 mutant with glutamic residues substituted at positions 744 and 748 as phospho-mimics (PKD-S744E/ S748E) is constitutively active when expressed in Cos7 or HeLa cells. The present study reveals that Ser-744/ Ser-748 phosphorylation is required for PKD1 activation in lymphocytes. However, PKD-S744E/S748E is not constitutively active but, like the wild type enzyme, requires antigen receptor triggering or phorbol ester stimulation. Antigen receptor activation of wild type PKD is dependent on phospholipase C (PLC)/diacylglycerol (DAG) and PKC, whereas PKD-S744E/S748E is only dependent on PLC/DAG but no longer requires PKC. Hence, substitution of serines 744 and 748 with glutamic residues as phospho-mimics bypasses the PKC requirement for PKD1 activation but does not bypass the need for antigen receptors, PLC, or DAG. In lymphocytes, PKD1 is, thus, not regulated by PLC and PKC in a linear pathway; rather, PKD1 activation has more stringent requirements for integration of dual PLC signals, one mediated by PKCs and one that is PKC-independent.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Wood

Marklund

Cantrell

2005

Journal of Biological Chemistry

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“…Mutations in the PH domain can activate PKD1 [17,24,25] . Deletion of the two zinc-fi ngers also fully activates PKD1 [26,27] .…”

Section: The Pkd Family Belongs To the Camk Groupmentioning

confidence: 99%

“…Mutations in the PH domain can activate PKD1 [17,24,25] . Deletion of the two zinc-fi ngers also fully activates PKD1 [26,27] .PKD transportation to different destinations, such as the plasma membrane, nucleus, or Golgi apparatus, in response to different signaling pathways, is largely dependent on the interactions of the PKD regulatory domains with lipids or proteins. In resting cells, PKD is mostly located in the cytosol, with a smaller fraction in the Golgi apparatus.…”

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confidence: 99%

Protein kinase D: a new player among the signaling proteins that regulate functions in the nervous system

Wang

2014

Neurosci. Bull.

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Protein kinase D (PKD) is an evolutionarily-conserved family of protein kinases. It has structural, regulatory, and enzymatic properties quite different from the PKC family. Many stimuli induce PKD signaling, including G-protein-coupled receptor agonists and growth factors. PKD1 is the most studied member of the family. It functions during cell proliferation, differentiation, secretion, cardiac hypertrophy, immune regulation, angiogenesis, and cancer. Previously, we found that PKD1 is also critically involved in pain modulation. Since then, a series of studies performed in our lab and by other groups have shown that PKDs also participate in other processes in the nervous system including neuronal polarity establishment, neuroprotection, and learning. Here, we discuss the connections between PKD structure, enzyme function, and localization, and summarize the recent fi ndings on the roles of PKD-mediated signaling in the nervous system. Keywords: PKD; neuronal polarity; pain modulation; neuroprotection; learning IntroductionMembers of the protein kinase D (PKD) family are diacylglycerol (DAG) and protein kinase C (PKC) effectors.They are activated by the actions of hormones, growth factors, neurotransmitters, and other stimuli through phospholipase C (PLC) [1] . Three widely-expressed mammalian homologs are PKD1 (mouse PKD, human PKCμ) [2,3] , PKD2 [3] , and PKD3 [4] (also named PKC), but the levels of individual PKDs vary in different tissues.Recent fi ndings have revealed that PKDs participate in the regulation of Golgi function through modulating the fi ssion of vesicles from the trans-Golgi network (TGN) [5,6] . Other recent reports have shown that PKDs function during cell proliferation and apoptosis, carcinogenesis, and intracellular trafficking. Here, we describe the connections between PKD structure, enzymatic function, and localization, and then summarize recent fi ndings on the roles of PKD in the nervous system. The PKD Family Belongs to the CaMK GroupThe PKD family comprises PKD1, PKD2, and PKD3. PKD was initially described as an atypical isoform of the PKC family [7] , which is a member of the protein kinase A, G, and C (AGC) serine/threonine kinase subfamily [8,9] . However, later studies revealed that PKD has mixed features of different subclasses of the PKC family, so it does not belong to any one of them. For example, its pleckstrin-homology (PH) domain is closely related to the PKB and G-proteincoupled receptor kinase (GRK) families and is not found in any PKC enzyme, while the cysteine-rich domains are more reminiscent of classical and novel PKCs. The structure and function of the catalytic domain of PKD are quite different from those of the AGC/PKC family members [2][3][4]10] . Indeed, PKD has now been classified as a new family within the (Fig. 1). The elaborate constitution of PKD1 is intricately linked to its catalytic functions, regulation, and intracellular localization (Table 1). PKD1 can be activated through different pathways.First, some stimuli activate PLC, which induces PKD phosp...

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Vasopressin‐induced intracellular redistribution of protein kinase D in intestinal epithelial cells

Rey

Zhukova

Sinnett‐Smith

2003

Journal Cellular Physiology

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The spatio-temporal changes of signaling molecules in response to G protein-coupled receptors (GPCR) stimulation is a poorly understood process in intestinal epithelial cells. Here we investigate the dynamic mechanisms associated with GPCR signaling in living rat intestinal epithelial cells by characterizing the intracellular translocation of protein kinase D (PKD), a serine/threonine protein kinase involved in mitogenic signaling in intestinal epithelial cells. Analysis of the intracellular steady-state distribution of green fluorescent protein (GFP)-tagged PKD indicated that in non-stimulated IEC-18 cells, GFP-PKD is predominantly cytoplasmic. However, cell stimulation with the GPCR agonist vasopressin induces a rapid translocation of GFP-PKD from the cytosol to the plasma membrane that is accompanied by its activation via protein kinase C (PKC)-mediated process and posterior plasma membrane dissociation. Subsequently, active PKD is imported into the nuclei where it transiently accumulates before being exported into the cytosol by a mechanism that requires a competent Crm1 nuclear export pathway. These findings provide evidence for a mechanism by which PKC coordinates in intestinal epithelial cells the translocation and activation of PKD in response to vasopressin-induced GPCR activation.

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Dissimilar phorbol ester binding properties of the individual cysteine‐rich motifs of protein kinase D

Cited by 59 publications

References 30 publications

Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Protein kinase D: a new player among the signaling proteins that regulate functions in the nervous system

Vasopressin‐induced intracellular redistribution of protein kinase D in intestinal epithelial cells

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