New PKCδ family members, PKCδIV, δV, δVI, and δVII are specifically expressed in mouse testis

Kawaguchi, T.; Niino, Yuko S.; Ohtaki, Hirokazu; Kikuyama, Sakaé; Shioda, Seiji

doi:10.1016/j.febslet.2006.03.084

Cited by 14 publications

(13 citation statements)

References 45 publications

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“…The occurrence of PKC␦ isoforms is species-specific. PKC␦I is ubiquitously present in all species while PKC␦II, -␦IV, -␦V, -␦VI, and -␦VII isoforms are present in mouse tissues (15,16); PKC␦III is present in rats (17) and PKC␦VIII is present in humans (1).…”

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confidence: 99%

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

Apostolatos

Vickers

et al. 2010

Journal of Biological Chemistry

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Vitamin A metabolite, all-trans-retinoic acid (RA), induces cell growth, differentiation, and apoptosis and has an emerging role in gene regulation and alternative splicing events. Protein kinase C␦ (PKC␦), a serine/threonine kinase, has a role in cell proliferation, differentiation, and apoptosis. We reported an alternatively spliced variant of human PKC␦, PKC␦VIII that functions as a pro-survival protein (1). RA regulates the splicing and expression of PKC␦VIII via utilization of a downstream 5 splice site of exon 10 on PKC␦ pre-mRNA. Here, we further elucidate the molecular mechanisms involved in RA regulation of alternative splicing of PKC␦VIII mRNA. Overexpression and knockdown of the splicing factor SC35 (i.e. SRp30b) indicated that it is involved in PKC␦VIII alternative splicing. To identify the cis-elements involved in 5 splice site selection we cloned a minigene, which included PKC␦ exon 10 and its flanking introns in the pSPL3 splicing vector. Alternative 5 splice site utilization in the minigene was promoted by RA. Further, co-transfection of SC35 with PKC␦ minigene promoted selection of 5 splice site II. Mutation of the SC35 binding site in the PKC␦ minigene abolished RA-mediated utilization of 5 splice splice II. RNA binding assays demonstrated that the enhancer element downstream of PKC␦ exon 10 is a SC35 cis-element. We conclude that SC35 is pivotal in RA-mediated PKC␦ pre-mRNA alternative splicing. This study demonstrates how a nutrient, vitamin A, via its metabolite RA, regulates alternative splicing and thereby gene expression of the pro-survival protein PKC␦VIII.Vitamin A, an important micronutrient and its active metabolite all-trans-retinoic acid (RA) 2 influence a broad range of physiological and pathological processes in the embryonic central nervous system and in the mature brain. Protein kinase C (PKC), a serine/threonine kinase family, consists of 11 isoforms and their splice variants and is involved in the regulation of cellular differentiation, growth, and apoptosis (2). Protein kinase C␦, a member of the novel PKC subfamily, is implicated in both apoptosis (3-10) and cell survival pathways (11-14) Thus, PKC␦ has dual effects and represents a switch that determines cell survival and fate. This can be explained by the expression of alternatively spliced variants of PKC␦ with distinct functions in the apoptotic cascade. The occurrence of PKC␦ isoforms is species-specific. PKC␦I is ubiquitously present in all species while PKC␦II, -␦IV, -␦V, -␦VI, and -␦VII isoforms are present in mouse tissues (15, 16); PKC␦III is present in rats (17) and PKC␦VIII is present in humans (1).An important mechanism of regulating gene expression occurs by alternative splicing which expands the coding capacity of a single gene to produce different proteins with distinct functions (18). It is now established that close to 90% of human genes undergo alternative splicing and encode for at least two isoforms. Divergence observed in gene expression because of alternative splicing may be tissue-specific (19,20), de...

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confidence: 99%

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

Apostolatos

Vickers

et al. 2010

Journal of Biological Chemistry

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“…Second, while PKC␦-⌬C2 was used in this study as a molecular tool to interrogate the structural determinants that regulate PKC␦ catalytic activity, this construct resembles a truncated PKC␦ isoform that is expressed in a developmentally regulated manner as a result of alternative splicing in mouse testis (31). Since disease-specific changes in PKC␦ mRNA splicing have recently been identified in certain heart failure phenotypes (32,33), a truncated PKC␦ isoform might be a component of the altered cardiac transcriptome that contributes to pathological cardiac stress responses.…”

Section: Discussionmentioning

confidence: 99%

The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser³⁵⁹ Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity

Gong

Yao

Zhang

et al. 2015

Molecular and Cellular Biology

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The diverse roles of protein kinase C-δ (PKCδ) in cellular growth, survival, and injury have been attributed to stimulus-specific differences in PKCδ signaling responses. PKCδ exerts membrane-delimited actions in cells activated by agonists that stimulate phosphoinositide hydrolysis. PKCδ is released from membranes as a Tyr(313)-phosphorylated enzyme that displays a high level of lipid-independent activity and altered substrate specificity during oxidative stress. This study identifies an interaction between PKCδ's Tyr(313)-phosphorylated hinge region and its phosphotyrosine-binding C2 domain that controls PKCδ's enzymology indirectly by decreasing phosphorylation in the kinase domain ATP-positioning loop at Ser(359). We show that wild-type (WT) PKCδ displays a strong preference for substrates with serine as the phosphoacceptor residue at the active site when it harbors phosphomimetic or bulky substitutions at Ser(359.) In contrast, PKCδ-S359A displays lipid-independent activity toward substrates with either a serine or threonine as the phosphoacceptor residue. Additional studies in cardiomyocytes show that oxidative stress decreases Ser(359) phosphorylation on native PKCδ and that PKCδ-S359A overexpression increases basal levels of phosphorylation on substrates with both phosphoacceptor site serine and threonine residues. Collectively, these studies identify a C2 domain-pTyr(313) docking interaction that controls ATP-positioning loop phosphorylation as a novel, dynamically regulated, and physiologically relevant structural determinant of PKCδ catalytic activity.

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“…Additional PKC isoforms are products of alternative splicing of the PKCβ [14] and PKCδ genes [15][16][17]. Members of the first subfamily, which include the conventional PKC (cPKC) isoforms, PKCα, β, and γ, are regulated via two DAG-binding C1 domains organized in tandem near the cPKC amino terminus [18][19][20], and an adjacent Ca 2+ and phospholipid-binding C2 domain [19,21].…”

Section: The Pkc Family Of Serine/threonine Kinasesmentioning

confidence: 99%

WASp and WAVE Proteins: From Structure, Through Function, to Clinical Aspects

Isakov¹

2013

J Clin Cell Immunol

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The protein kinase C-theta (PKCθ) isoform is a member of the calcium-independent novel PKC subfamily of serine/threonine kinases. It is an essential regulatory enzyme in mature T lymphocytes, where it plays a key role in coupling the activated TCR and the CD28 costimulatory receptor to their downstream signaling pathways. TCR/ CD28 engagement induces the translocation of PKCθ to the center of the immunological synapse where it undergoes posttranslational modifications and becomes fully active. The activated PKCθ then initiates signaling pathways leading to the activation of transcription factors, including NF-κB, AP-1 and NF-AT that are essential for the survival, activation and differentiation of T cells. While PKCθ ablation was found to impair a wide range of in vitro responses of T cells, in vivo studies in Prkcq -/mice revealed that distinct T cell subpopulations differ in their requirements for PKCθ and that PKCθ has a selective role in different immune responses. Thus, PKCθ participates in cellular mechanisms leading to excessive inflammatory responses, autoimmunity, and graft vs host (GvH) disease, but is dispensable for beneficial immune responses against viruses and during graft vs leukemia responses. These studies suggest that PKCθ may serve as a potential drug target for catalytic and allosteric inhibitors in selected T cell-mediated diseases, and that fine-tuning of PKCθ-dependent functions may help prevent autoimmunity and GvH, without impairing the ability of T cells to eradicate viral-infected and transformed cells. PKCθPKCθ is a member of the novel PKC subfamily, initially isolated from T cells, skeletal muscle and platelets [25][26][27]. Additional studies demonstrated that PKCθ exhibits a relatively restricted pattern of expression, with high levels in T lymphocytes [23,25], platelets [27][28][29][30] Citation: Isakov N (2012) PKCθ is a Key Regulator of T-cell Behavior and a Drug Target for T cell-mediated Diseases.

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New PKCδ family members, PKCδIV, δV, δVI, and δVII are specifically expressed in mouse testis

Cited by 14 publications

References 45 publications

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser³⁵⁹ Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity

WASp and WAVE Proteins: From Structure, Through Function, to Clinical Aspects

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New PKCδ family members, PKCδIV, δV, δVI, and δVII are specifically expressed in mouse testis

Cited by 14 publications

References 45 publications

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

Vitamin A Metabolite, All-trans-retinoic Acid, Mediates Alternative Splicing of Protein Kinase C δVIII (PKCδVIII) Isoform via Splicing Factor SC35

The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser359 Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity

WASp and WAVE Proteins: From Structure, Through Function, to Clinical Aspects

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The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser³⁵⁹ Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity