Dual role of protein kinase C on mitogen‐activated protein kinase activation and human keratinocyte proliferation

Praskova, Maria; Kalenderova, Silvia; Miteva, Ljubka; Poumay, Yves; Mitev, В.

doi:10.1034/j.1600-0625.2002.110408.x

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…The activation of the IP 3 pathway, leading to intracellular calcium rise, is now accepted to be a key pathway linking intracellular Ca 2ϩ rise to ERK1/2 phosphorylation (15). Subsequent activation of CaM kinase II has also been linked to ERK1/2 activation in keratinocytes (14,54,55). Similarly, in the brain, this kinase plays a fundamental role in neuronal development and function (56 -59).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+ Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Azriel-Tamir

Sharir²,

Schwartz

et al. 2004

Journal of Biological Chemistry

120

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Extracellular zinc promotes cell proliferation and its deficiency leads to impairment of this process, which is particularly important in epithelial cells. We have recently characterized a zinc-sensing receptor (ZnR) linking extracellular zinc to intracellular release of calcium. In the present study, we addressed the role of extracellular zinc, acting via the ZnR, in regulating the MAP kinase pathway and Na Arrested cell proliferation is a hallmark of zinc deficiency. This is particularly true in gastrointestinal cells (1-4), where insufficient dietary zinc attenuates the renewal of the epithelium leading to severe diarrhea (1). Extracellular zinc has been shown to regulate cell proliferation via the MAP 1 kinase pathway in several cell types (5-7). Although the mitogenic and anti-apoptotic effects of zinc are well recognized (8, 9), and the treatment of severe diarrhea by addition of dietary zinc is common, the direct link between this ion and the cellular mechanisms regulating proliferation is not well understood. It has been suggested that a decrease in intracellular zinc may lead directly to a reduction in activity of various metalloenzymes involved in transcription and cell metabolism (1, 10). Several studies, however, indicate that extracellular zinc acts as a signaling molecule. In tracheal cells, for example, extracellular zinc, through activation of Src, leads to transactivation of EGFR and subsequently to activation of ERK1/2 (11). In fibroblasts, extracellular zinc has been shown to trigger the activation of the PI3K pathway, subsequently leading to the activation of AKT and the S6 kinase (12). The signaling pathways linking extracellular zinc to these proteins and to subsequent regulation of cellular ion, pH or volume homeostasis, however, remain poorly understood.We have recently identified and characterized an extracellular zinc-sensing receptor (ZnR) that triggers, upon exposure to extracellular zinc, the release of Ca 2ϩ from intracellular stores by activation of the IP 3 pathway (13). The pharmacological profile of the calcium response triggered by the ZnR, particularly its sensitivity to the PLC inhibitor, U73122, and the inhibitory effect of the IP 3 receptor blocker, 2-APB, indicates that the ZnR is a G q -coupled receptor (GPCR). Both the G␣ and the G␤␥ dimer of various GPCRs have been linked to activation of the MAP kinase via multiple intracellular pathways (14 -16). In intestinal cells, furthermore, the muscarinic receptor has been shown to play a key role in promoting ion transport through activation of MAP and PI 3-kinase signal transduction (17,18). A role for the ZnR in activation of the MAP kinase pathway is demonstrated in this work.The ZnR was initially characterized in the colonocytic cell line, HT29, where a robust calcium signal was generated following activation of the receptor by changes in the concentration of extracellular Zn 2ϩ (13). Importantly, the Ca 2ϩ response induced by the ZnR in HT29 cells is triggered by ϳ80 M zinc, i.e. within the physiological range of zinc conc...

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Section: Discussionmentioning

confidence: 99%

Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+ Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Azriel-Tamir

Sharir²,

Schwartz

et al. 2004

Journal of Biological Chemistry

120

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“…Conditioned medium (CM) produced by NHKs stimulates DNA synthesis in a way that can be partially blocked with antibodies against various ErbB ligands and strongly blocked by antibodies against ErbB1 (Coffey et al, 1987;Cook et al, 1991a;Pittelkow et al, 1993Pittelkow et al, , 1994Hashimoto et al, 1994;Shirakata et al, 2000). Moreover, we and others have observed that it is very difficult to obtain proliferative quiescence in NHKs by removal of growth factors (GFs) (Coffey et al, 1987;Klein et al, 1992;Praskova et al, 2002). Together, these findings are strongly suggestive of an autocrine mechanism of ErbB activation in NHKs.…”

Section: Introductionmentioning

confidence: 99%

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Kansra

Stoll

Johnson

et al. 2004

MBoC

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ErbB signaling through extracellular signal-regulated kinase (ERK) has been implicated in regulating the expression of ErbB ligands in hyperproliferative skin disorders and wound healing. Here, we characterize the process of autocrine ERK activation in cultured normal human keratinocytes (NHKs) subjected to growth factor (GF) deprivation. Basal ERK phosphorylation was lower after 48 h than after 24 h of GF deprivation, and lowest at 30 -60 min after an additional medium change. ERK phosphorylation was markedly increased by low concentrations of epidermal growth factor (EGF) (0.2-1 ng/ml) that provoked only a limited increase in ErbB1 tyrosine phosphorylation and internalization. Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing monoclonal antibody 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR). In contrast, these responses were unaffected by neutralizing antibodies against other ErbB1 ligands or the ErbB2 inhibitors geldanamycin and AG825. The time course of autocrine ERK phosphorylation correlated with the appearance of soluble AR, and two different metalloproteinase inhibitors blocked AR release. These results define an amphiregulin-and ErbB1-dependent mechanism by which autocrine ERK activation is maintained in NHKs, even when ErbB1 autophosphorylation and internalization are limited. INTRODUCTIONThe mammalian c-ErbB family is comprised of four closely related receptor tyrosine kinases (RTKs) that interact hierarchically in response to multiple ErbB receptor ligands (Klapper et al., 2000;Olayioye et al., 2000). Ligand binding to the extracellular domain promotes receptor homo-and heterodimerization, resulting in phosphorylation of specific tyrosine residues on the cytoplasmic domain. These events lead to activation of multiple signal transduction pathways via Src homology 2 (SH2)-and phosphotyrosine binding (PTB)-domain containing cytoplasmic proteins, ultimately affecting many cellular functions, including cell migration, proliferation, and differentiation (Hubbard et al., 1998;Hackel et al., 1999). We and others have demonstrated that human skin expresses ErbB1, ErbB2, and ErbB3, but little or no ErbB4 (Press et al., 1990;Prigent et al., 1992;De Potter et al., 2001;Stoll et al., 2001).ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al., 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al., 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al., 1998), and epiregulin (Draper et al., 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al., 2001). Organ cultures of skin display many features of early wounds, including rapid keratinocyte cytoskeletal alterations, an early ...

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“…Consistent with this role, studies from our group show that the novel PKC (nPKC) isoforms stimulate keratinocyte differentiation by activating MAPK signaling, which results in increased nuclear levels of AP1, CCAAT enhancer-binding protein, and Sp1 transcription factors and binding of these factors to target genes to increase transcription (27)(28)(29). Involucrin is a classical marker of differentiation, and our studies show that PKC␦ is a potent activator of involucrin expression (21, 27, 30 -32).PKC isoforms have also been implicated in the regulation of keratinocyte proliferation (13,20,23,(33)(34)(35). This role is particularly important, because keratinocyte differentiation is associated with cessation of proliferation, and it would make mechanistic sense to have a common kinase activate both processes.…”

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confidence: 97%

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

Chew

Adhikary

Wilson

et al. 2011

Journal of Biological Chemistry

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PKC␦ increases keratinocyte differentiation and suppresses keratinocyte proliferation and survival. However, the mechanism of proliferation suppression is not well understood. The present studies show that PKC␦ overexpression increases p21Cip1 mRNA and protein level and promoter activity and that treatment with dominant-negative PKC␦, PKC␦-siRNA, or rottlerin inhibits promoter activation. Analysis of the p21Cip1 promoter upstream regulatory region reveals three DNA segments that mediate PKC␦-dependent promoter activation. The PKC␦ response element most proximal to the transcription start site encodes six GC-rich DNA elements. Mutation of these sites results in a loss of PKC␦-dependent promoter activation. Gel mobility supershift and chromatin immunoprecipitation reveal that these DNA elements bind the Kruppel-like transcription factor KLF4. PKC␦ increases KLF4 mRNA and protein level and KLF4 binding to the GC-rich elements in the p21 Cip1 proximal promoter. In addition, KLF4-siRNA inhibits PKC␦-dependent p21 Cip1 promoter activity. PKC␦ increases KLF4 expression leading to enhanced KLF4 interaction with the GC-rich elements in the p21 Cip1 promoter to activate transcription.PKC isoforms include three subfamilies of kinases that play a central role in the regulation of cell growth and differentiation (1). Classical PKCs (␣, ␤, and ␥) are calcium-, phospholipid-, and diacylglycerol-dependent; novel PKCs (nPKC ␦, ⑀, , and ) 2 are activated by diacylglycerol and phospholipids, but they do not respond directly to calcium; and atypical PKCs ( and ) are calcium-and diacylglycerol-independent but undergo allosteric activation (2, 3). Epidermal keratinocytes express PKC␣, ␤II, ␦, ⑀, , and (4 -10). These kinases have been studied in cultured keratinocytes and in animal models (11)(12)(13)(14)(15)(16)(17)(18)(19). A number of laboratories have shown that nPKC isoforms stimulate keratinocyte differentiation (15, 20 -24, 26). Consistent with this role, studies from our group show that the novel PKC (nPKC) isoforms stimulate keratinocyte differentiation by activating MAPK signaling, which results in increased nuclear levels of AP1, CCAAT enhancer-binding protein, and Sp1 transcription factors and binding of these factors to target genes to increase transcription (27)(28)(29). Involucrin is a classical marker of differentiation, and our studies show that PKC␦ is a potent activator of involucrin expression (21, 27, 30 -32).PKC isoforms have also been implicated in the regulation of keratinocyte proliferation (13,20,23,(33)(34)(35). This role is particularly important, because keratinocyte differentiation is associated with cessation of proliferation, and it would make mechanistic sense to have a common kinase activate both processes. A limited number of studies have examined the mechanism of nPKC regulation of keratinocyte proliferation. For example, the nPKC isoform PKC⑀ binds to and activates Fyn, a Src kinase, and this is associated with reduced keratinocyte proliferation (36). PKC⑀ forms a complex with cyclin E-cdk2-p21Cip1...

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Dual role of protein kinase C on mitogen‐activated protein kinase activation and human keratinocyte proliferation

Cited by 15 publications

References 26 publications

Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+ Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+ Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

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