PKC epsilon-related kinase associates with and phosphorylates cytokeratin 8 and 18.

Omary, M. Bishr; Baxter, Gregory T.; Chou, Chia-Fu; Riopel, C L; Lin, Wei‐Qi; Strulovici, Berta

doi:10.1083/jcb.117.3.583

Cited by 91 publications

(54 citation statements)

References 56 publications

(81 reference statements)

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“…It is known that protein phosphatases are important regulators of steady-state cytokeratin phosphorylation. 20,40,60,64 Furthermore, different turnover rates were identified for the various phosphorylation sites on CK8 and CK18. 48 In contrast to CK8, which showed a higher steady-state phosphorylation in a variety of situations, including chronic intoxication of mice with GF or stimulation of PKC in cultured hepatocytes, CK18 had a lower steady state phosphorylation level because of rapid dephosphorylation by protein phosphatases.…”

Section: Discussionmentioning

confidence: 99%

“…34 -36 Cytokeratins undergo several posttranslational modifications, such as phosphorylation, glycosylation, acetylation, and transglutaminase-induced cross-linking, that are likely to be involved in regulating their function. [37][38][39][40][41] In the case of CK8/18, phosphorylation has been extensively studied in cultured cells and in vitro experiments. Phosphorylation of cytokeratins and other IF proteins plays important roles in the cell, 41 including regulation of filament disassembly and reorganization, particularly during mitosis, solubility, interaction with other proteins, and determining localization within specific compartments of the cell.…”

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confidence: 99%

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Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

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Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies , termed Mallory bodies (MBs).Cytokeratins are members of the large family of intermediate filament (IF) cytoskeletal proteins, which are normally expressed in a tissue-specific manner and assembled as cytoplasmic filamentous arrays. Neurofilaments, ␣-internexin, desmin, vimentin, glial filaments, and the nuclear lamins 1,2 also belong to the IF family. The diverse cell biological functions of IFs are still poorly understood. However, a diversity of human diseases is associated with severe alterations of IFs. A common pathological feature of many IF-related diseases is the accumulation of intracytoplasmic inclusions consisting of modified IF proteins, for example in neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Lewy body dementia 3-6 ; in neuromuscular disorders (eg, spheroid body myositis 7 ); and the formation of Mallory bodies (MBs) in alcoholic hepatitis (AH) and other liver disorders (eg, non-alcoholic steatohepatitis, Wilson's disease, primary biliary cirrhosis, Indian childhood cirrhosis, hepatocellular neoplasms 8 -11 ). Although the underlying pathogenetic mechanisms are as yet unclear, posttranslational modifications of IF proteins, such as phosphorylation, limited proteolysis, and crosslinking, may play a major role. For example, the presence of hyperphosphorylated neurofilament epitopes in some neuronal inclusion bodies 12-15 and of abnormally phosphorylated desmin in muscle fibers 16 were reported. Furthermore, a possible association of cytokeratin hyperphosphorylation with the formation of MBs in hepatocytes, a hallmark of AH, was suggested by in vitro and animal studies performed by our own group and others. [17][18][19][20] AH follows chronic alcohol abuse and occurs in 20 to 40% of heavy drinkers. Although reversible at the beginning, most cases of AH progress to irreversible cirrhosis. Besides the amount of alcohol ingested per day, a variety of other factors such as dietary habits, genetic factors influencing alcohol metabolism, viral infections, and additional toxins or drugs seem to determine the extent of liver damage. Classical morphological features of AH are liver cell ballooning and necrosis, inflammation, steatosis, and the formation of cytokeratin-containing MBs, which is associated with severe derangement (ie, diminution or even loss) of the hepatocyte cytokeratin IF network. 8 -11,22-26 Diverse animal models have been generated to study in more detail and under defined conditions mechanisms involved in the pathogenesis of this alcoholic liver disease. Experimental long-term intoxication of mice with Supported by the grants of the Austrian Science Foundation S7401-MOB (to K. Z.) and 7628-MED (to H. D.) and by a U.S. Veterans Affairs Merit and Career Development Award (to M. B. O.).

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

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“…cytokeratins 8/18 (Chou & Omary, 1991). An isoform (PKC epsilon)-related kinase associates with and phosphorylates cytokeratins 8 and 18 (Omary et al, 1992). As the cytoskeleton controls cell shape and locomotion it will be of interest to test PKC inhibitors with regard to PKC subspecies.…”

Section: Discussionmentioning

confidence: 99%

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells

Zimmermann

Keller²

1992

Br J Cancer

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Summary The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (IDm of about 6.0 x 10-8 M) as well as spontaneous and colchicine-stimulated locomotion at 10-7 M. K 252a suppresses cell polarity (IDm of about 4.5 x 10-6 M) and inhibits spontaneous and colchicinestimulated locomotion at I0-I M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K 252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotidedependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.

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“…For example, K8/K18 bind to tumor necrosis factor (TNF) receptor 2 and Raf-1 kinase (Omary et al, 1992;Liao and Omary, 1996;Caulin et al, 2000;Ku et al, 2004a). In addition, keratin-deficient endodermal cells exhibit increased nuclear factor (NF)-B and c-Jun NH 2 -terminal kinase activation in response to TNF-␣ (Caulin et al, 2000).…”

Section: Potential Signaling Pathways Regulating Reg-ii Expression Inmentioning

confidence: 99%

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

Zhong

Strnad

Toivola

et al. 2007

MBoC

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The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation. INTRODUCTIONIntermediate filaments (IFs), microfilaments, and microtubules are the three major cytoskeletal protein groups of mammalian cells (Bershadsky and Vasiliev, 1988;Ku et al., 1999). All IFs share a common prototype structure consisting of a coiled-coil ␣-helical rod domain that is interrupted by linkers and flanked by non-␣-helical N-terminal "head" and C-terminal "tail" domains (Fuchs and Cleveland, 1998;Herrmann et al., 2003;Coulombe and Wong, 2004;Herrmann and Aebi, 2004). Within the IF family, keratins are the largest subfamily, and they make up the IFs of epithelial cells, whereas other IFs are characteristic of unique cell types (e.g., desmin in myocytes, neurofilaments in neuronal cells). This tissue-specific expression reflects the involvement of IFs in a broad range of tissue-selective human diseases (Fuchs and Cleveland, 1998;Omary et al., 2004). Keratins (K) include the type I and type II IFs, and all epithelial cells express at least one type I and one type II keratins as obligate noncovalent heteropolymers (Moll et al., 1982;Schweizer et al., 2006). In simple-type epithelia, as found in the liver, pancreas, and intestine, the major keratins are K18/K19/K20 (type I) and K7/K8 (type II), with the K8/K18 pair being dominant depending on the tissue (Moll et al., 1982;Ku et al., 1999;Herrmann et al., 2003;Zhou et al., 2003).Keratin networks are versatile structures that undergo dynamic reorganization in response to a variety of intra-and extracellular cues. Posttranslational modifications and keratin-binding partners...

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PKC epsilon-related kinase associates with and phosphorylates cytokeratin 8 and 18.

Cited by 91 publications

References 56 publications

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

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