Physical association and functional relationship between protein kinase Cζ and the actin cytoskeleton

Gómez, Javier; Aragón, Ana Martínez de; Bonay, Pedro; Pitton, Christina; García, Alphonse; Silva, Augusto; Fresno, Manuel; Álvarez, Fernando; Rebollo, Angelita

doi:10.1002/eji.1830250941

Cited by 64 publications

(53 citation statements)

References 40 publications

(6 reference statements)

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“…When we stimulate granule release with 12-O-tetradecanoylphorbol-13-acetate and ionomycin to bypass proximal signaling pathways, granule release is inhibited from cells expressing recombinant Itk (data not shown), which is consistent with a potential inhibitory role for Itk in downstream signaling subsequent to calcium. Possibilities include the activation of specific PKC family members, isoforms of which may interact directly or indirectly with Tec family kinases (47,48). In addition, novel PKC isoforms, which do not rely on calcium for their activation, have been implicated as negative regulators of secretion in other cell types (49,50).…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that, in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Itk), differentially regulates distinct NK-activating receptors. Enhanced expression of Itk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Itk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Itk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Itk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Itk is required for both the positive and negative regulation of these pathways. Complementary experiments where Itk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Itk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles.

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Section: Discussionmentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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“…For example, PKC, which is highly expressed in T cells, has been extensively documented to play essential roles in T cell activation, signaling, and gene transcription regulation (45). In addition, PKC␤ has been suggested to be a key element in proper T cell migration (46), while PKC has been described as maintaining the integrity of the actin cytoskeleton and mediating interleukin-induced T cell proliferation (47). It is also noteworthy that gold sodium thiomalate, which has been used as a therapeutic agent for RA for many years, is now recognized as a PKC inhibitor, suppressing mitogen-induced T cell proliferation (48).…”

Section: Discussionmentioning

confidence: 99%

Genetic association between the PRKCH gene encoding protein kinase Cη isozyme and rheumatoid arthritis in the Japanese population

Takata¹,

Hamada²,

Miyatake³

et al. 2007

Arthritis & Rheumatism

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Objective. Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q21-23. This large population-based genetic association study was undertaken to examine this region.Methods. A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using >400 genebased common single-nucleotide polymorphisms (SNPs).Results. Multiple SNPs in the PRKCH gene encoding the isozyme of protein kinase C (PKC) showed significant single-locus disease associations, the most significant being SNP c.427؉8134C>T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P ‫؍‬ 5.9 ؋ 10 ؊5 ). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4؉ or CD8؉) than in B cells (CD19؉) or monocytes (CD14؉) and was significantly down-regulated through immune responses.Conclusion. Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKC signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.

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“…The PKC assay system (catalog #V7470) was from Promega (Madison, WI). Phosphorothioate PKC antisense and scrambled control oligonucleotides have been previously reported (27,28) and were synthetized by PRIMM (Milan, Italy). PKC DN and wild-type cDNAs were generous gifts of Dr. S. Gutkind (NCI, National Institutes of Health, Bethesda, MD).…”

Section: Methodsmentioning

confidence: 99%

Insulin Receptor Substrate-2 Phosphorylation Is Necessary for Protein Kinase Cζ Activation by Insulin in L6hIR Cells

Oriente

Formisano

Miele

et al. 2001

Journal of Biological Chemistry

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We have investigated glycogen synthase (GS) activation in L6hIR cells expressing a peptide corresponding to the kinase regulatory loop binding domain of insulin receptor substrate-2 (IRS-2) (KRLB). In several clones of these cells (B2, F4), insulin-dependent binding of the KRLB to insulin receptors was accompanied by a block of IRS-2, but not IRS-1, phosphorylation, and insulin receptor binding. GS activation by insulin was also inhibited by >70% in these cells (p < 0.001). The impairment of GS activation was paralleled by a similarly sized inhibition of glycogen synthase kinase 3␣ (GSK3␣) and GSK3␤ inactivation by insulin with no change in protein phosphatase 1 activity. PDK1 (a phosphatidylinositol trisphosphate-dependent kinase) and Akt/protein kinase B (PKB) activation by insulin showed no difference in B2, F4, and in control L6hIR cells. At variance, insulin did not activate PKC in B2 and F4 cells. In L6hIR, inhibition of PKC activity by either a PKC antisense or a dominant negative mutant also reduced by 75% insulin inactivation of GSK3␣ and -␤ (p < 0.001) and insulin stimulation of GS (p < 0.002), similar to Akt/PKB inhibition. In L6hIR, insulin induced protein kinase C (PKC) co-precipitation with GSK3␣ and ␤. PKC also phosphorylated GSK3␣ and -␤. Alone, these events did not significantly affect GSK3␣ and -␤ activities. Inhibition of PKC activity, however, reduced Akt/PKB phosphorylation of the key serine sites on GSK3␣ and -␤ by >80% (p < 0.001) and prevented full GSK3 inactivation by insulin. Thus, IRS-2, not IRS-1, signals insulin activation of GS in the L6hIR skeletal muscle cells. In these cells, insulin inhibition of GSK3␣ and -␤ requires dual phosphorylation by both Akt/PKB and PKC.

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Physical association and functional relationship between protein kinase Cζ and the actin cytoskeleton

Cited by 64 publications

References 40 publications

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Genetic association between the PRKCH gene encoding protein kinase Cη isozyme and rheumatoid arthritis in the Japanese population

Insulin Receptor Substrate-2 Phosphorylation Is Necessary for Protein Kinase Cζ Activation by Insulin in L6hIR Cells

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