The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

LaGory, Edward L.; Sitailo, Leonid A.; Denning, Mitchell F.

doi:10.1074/jbc.m109.055392

Cited by 25 publications

(22 citation statements)

References 50 publications

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“…PKC␦ also has been implicated in endoplasmic reticulum stress (50,51). PKC␦ becomes associated to a Golgi compartment in the G 2 /M phase of the cell cycle, suggesting a role for perinuclear PKC␦ in the phosphorylation of mitotic kinases and growth arrest (52)(53)(54). Interestingly, perinuclear targeting of PKC␦ prevents apoptosis (23,45), which is consistent with the proapoptotic role of this kinase only when it is disassociated from p23.…”

Section: Discussionsupporting

confidence: 64%

p23/Tmp21 Associates with Protein Kinase Cδ (PKCδ) and Modulates Its Apoptotic Function

Wang¹,

Xiao²,

Kazanietz

2011

Journal of Biological Chemistry

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There is emerging evidence that C1 domains, motifs originally identified in PKC isozymes and responsible for binding of phorbol esters and diacylglycerol, interact with the Golgi/endoplasmic reticulum protein p23 (Tmp21). In this study, we investigated whether PKC␦, a kinase widely implicated in apoptosis and inhibition of cell cycle progression, associates with p23 and determined the potential functional implications of this interaction. Using a yeast two-hybrid approach, we found that the PKC␦ C1b domain associates with p23 and identified two key residues (Asp 245 and Met 266 ) implicated in this interaction. Interestingly, silencing p23 from LNCaP prostate cancer cells using RNAi markedly enhanced PKC␦-dependent apoptosis and activation of PKC␦ downstream effectors ROCK and JNK by phorbol 12-myristate 13-acetate. Moreover, translocation of PKC␦ to the plasma membrane by phorbol 12-myristate 13-acetate was enhanced in p23-depleted LNCaP cells. Notably, a PKC␦ mutant that failed to interact with p23 triggered a strong apoptotic response when expressed in LNCaP cells. In summary, our data compellingly support the concept that C1 domains have dual roles both in lipid and protein associations and provide strong evidence that p23 acts as an anchoring protein that retains PKC␦ at the perinuclear region, thus limiting the availability of this kinase for activation in response to stimuli. p23/Tmp21 (hereafter referred to as p23) is a type I transmembrane protein that belongs to the p24 endoplasmic reticulum/Golgi cargo family and plays critical roles in protein transport, organization of membrane structure, and the secretory pathway. Members of the p24 family have been widely implicated as COP (coat protein) vesicle cargo receptors, and they are involved in COP vesicle budding and the organization of the Golgi apparatus (1). In addition to the well established role of p23 in vesicle formation and cargo transport in the endoplasmic reticulum/Golgi (2-5), this protein has been implicated in several other cellular functions, including the recruitment of the small GTPase ADP-ribosylation factor 1 to the Golgi apparatus (6, 7) and ADP-ribosylation factor 1-dependent assembly of actin in the Golgi (8). p23 also is a component of the presenilin complex at the plasma membrane and modulates ␥-secretase cleavage (9).In a previous yeast two-hybrid screening, we established that p23 physically associates with ␣-and ␤-chimaerins, Rac GTPase-activating proteins (GAPs) 4 regulated by the lipid second messenger diacylglycerol (DAG) and DAG mimetic analogs such as the phorbol esters (10 -13). Mutational and deletional studies revealed that this interaction is mediated by the C1 domain present in chimaerins (10). The 50 -51-amino acid cysteine-rich C1 domains were identified originally in PKC isozymes as the sites for DAG and phorbol ester binding. C1 domains drive the recruitment of proteins to internal membranes and, in this manner, facilitate their access to docking proteins and effectors. More recently, we identified key residues w...

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Section: Discussionsupporting

confidence: 64%

p23/Tmp21 Associates with Protein Kinase Cδ (PKCδ) and Modulates Its Apoptotic Function

Wang¹,

Xiao²,

Kazanietz

2011

Journal of Biological Chemistry

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“…In addition, PKCδ knockdown abolishes DNA damage-induced apoptosis in various cells (47–49). Thus, we further investigated whether etoposide treatment induces PKCδ-mediated phosphorylation of hnRNPK at Ser302.…”

Section: Resultsmentioning

confidence: 99%

Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation

Yang¹,

Chiou²,

Fu³

et al. 2014

Nucleic Acids Research

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Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA-binding protein involved in chromatin remodeling, RNA processing and the DNA damage response. In addition, increased hnRNPK expression has been associated with tumor development and progression. A variety of post-translational modifications of hnRNPK have been identified and shown to regulate hnRNPK function, including phosphorylation, ubiquitination, sumoylation and methylation. However, the functional significance of hnRNPK arginine methylation remains unclear. In the present study, we demonstrated that the methylation of two essential arginines, Arg296 and Arg299, on hnRNPK inhibited a nearby Ser302 phosphorylation that was mediated through the pro-apoptotic kinase PKCδ. Notably, the engineered U2OS cells carrying an Arg296/Arg299 methylation-defective hnRNPK mutant exhibited increased apoptosis upon DNA damage. While such elevated apoptosis can be diminished through addition with wild-type hnRNPK, we further demonstrated that this increased apoptosis occurred through both intrinsic and extrinsic pathways and was p53 independent, at least in part. Here, we provide the first evidence that the arginine methylation of hnRNPK negatively regulates cell apoptosis through PKCδ-mediated signaling during DNA damage, which is essential for the anti-apoptotic role of hnRNPK in apoptosis and the evasion of apoptosis in cancer cells.

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“…Some studies place PKCδ upstream of the DNA damage sensors, DNA-dependent protein kinase, and ataxia telangiectasia mutated (ATM) and suggest a role for PKCδ in their activation in response to DNA damage (Bharti et al, 1998; Arango et al, 2012; Soriano-Carot, Quilis, Bano, & Igual, 2014). PKCδ has also been shown to function downstream of ATM activation (Li et al, 2004; LaGory, Sitailo, & Denning, 2010). Blocking PKCδ function inhibits phosphorylation of the ATM target, histone H2AX, a key regulator of the DNA damage response (Arango et al, 2012).…”

Section: Biological Functions Of Pkcδmentioning

confidence: 99%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

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The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

Cited by 25 publications

References 50 publications

p23/Tmp21 Associates with Protein Kinase Cδ (PKCδ) and Modulates Its Apoptotic Function

p23/Tmp21 Associates with Protein Kinase Cδ (PKCδ) and Modulates Its Apoptotic Function

Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

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