Protein Kinase C and its Role in Cell Growth

Woodgett, James R.; Hunter, Tony; Gould, Kathleen L.

doi:10.1007/978-1-4613-1915-3_6

Cited by 35 publications

(12 citation statements)

References 826 publications

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“…In contrast to TPA, these agents result in transient and substoichiometric phosphorylation of S12 in pp60csrc. This difference in kinetics can be explained by the transient, rather than prolonged, activation of protein kinase C by these agents and presumably by the restriction of protein kinase C activated by diacylglycerols to the plasma membrane (for a review, see reference 66), where not all pp60csrc molecules are located (55).…”

Section: Resultsmentioning

confidence: 99%

Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity.

Gould¹,

Hunter²

1988

Mol. Cell. Biol.

234

112

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We have shown previously that pp69>-sc is a substrate for protein kinase C in vitro and in vivo and that the target of protein kinase C phosphorylation in mammalian pp6OcSrc is serine 12. We now demonstrate that in addition to tumor promoters, all activators of phosphatidylinositol turnover that we have tested in fibroblasts (platelet-derived growth factor, fibroblast growth factor, serum, vasopressin, sodium orthovanadate, and prostaglandin F2.) lead to the phosphorylation of pp60c-sr at serine 12. In addition to stimulating serine 12 phosphorylation in pp6Oc-"s, platelet-derived growth factor treatment of quiescent fibroblasts induces phosphorylation of one or two additional serine residues and one tyrosine residue within the N-terminal 16 kilodaltons of the enzyme and activates its immune complex protein-tyrosine kinase activity.pp6f-src is a membrane-associated phosphoprotein with intrinsic protein-tyrosine kinase activity (for a review, see reference 32). It can be activated to transform cells by C-terminal truncation or various point mutations (6,35,36,40,49,56). pp60c,src is expressed ubiquitously in animal cells, in which its transforming potential is normally suppressed and its specific tyrosine protein kinase activity is lower than that of its transforming counterparts (24,34,45). The highest levels of pp6csrc have been found in the brain (21), platelets (28), peripheral blood lymphocytes (28), and adrenal medullary chromaffin cells (46). Although this distribution has suggested that pp60c-src functions in development, maintenance of a differentiated state, or secretion, its role in normal cellular physiology and its mode of regulation are not understood.We are interested in the role of phosphorylation in the regulation of pp6c-src function. Under most conditions, serine 17 (S17) is the major site of serine phosphorylation in pp60c-src (48, 61). pp60csrc is also phosphorylated in cells to near stoichiometry on a tyrosine near its C terminus, tyrosine 527 (Y527) in chicken pp60csrc (16). Phosphorylation of Y527 constrains the protein kinase activity of the molecule (18,22), and deletion or mutation of this residue results in a protein with transforming ability and higher protein kinase activity (6,36,49,56). Another tyrosine residue within pp60c-src, tyrosine 416 (Y416), is the major site of autophosphorylation in vitro (47, 61). In vivo, Y416 is phosphorylated when Y527 has been mutated (as in Y527 to phenylalanine 527) or deleted (as in pp60vsrc) (6,36,49,56). If it is assumed that pp60c-src is active as a protein kinase under certain circumstances in normal cells, a mechanism(s) must exist for activating and subsequently inhibiting its activity. Such regulation could be achieved by the transient dephosphorylation of Y527, but to date, there have been no reports that this occurs in nontransformed cells.We (29) and others (26, 62) have shown that pp60c src is phosphorylated rapidly and stoichiometrically at a normally unphosphorylated serine(s) when cells are treated with tumor promoters that bind and ...

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Section: Resultsmentioning

confidence: 99%

Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity.

Gould¹,

Hunter²

1988

Mol. Cell. Biol.

234

112

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“…A detailed computer analysis of smaller fragments in the NPAT product showed similarities with a large number of known protein motifs, enabling us to identify the region with possible functional importance. Notable were five consensus sequences for phosphorylation by CDK4/E2F and CDK6/E2F complexes (Ser/Thrpro-X-Lys/Arg) (Nigg 1993a), 24 protein kinase C phosphorylation target sites (Ser/Thr-X-Lys/Arg) (Kishimoto et al 1985;Woodgett et al 1986), and three cAMP/cGMP-dependent protein kinase phosphorylation target sequences (Lys/Arg-Lys/ Arg-X-Ser/Thr) (Feramisco et al 1980) (Fig. 4).…”

Section: Predicted Amino Acid Sequence Of Npatmentioning

confidence: 99%

Identification and characterization of a new gene physically linked to the ATM gene.

Imai¹,

Yamauchi²,

Seki³

et al. 1996

Genome Res.

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Ataxia telangiectasia [AT} is an autosomal recessive disease of unknown etiology associated with cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, and hypersensitivity to ionizing radiation. Although AT has been divided into four complementation groups by its radioresistant-DNA synthesis phenotype, the ATM gene has been isolated as the candidate gene responsible for all AT groups. We identified a new gene, designated NPAT, from the major AT locus on human chromosome Ilq22-q23. The gene encoded a 1421-amino-acid protein containing nuclear localization signals and phosphorylation target sites by cyclin-dependent protein kinases associated with E2F. The messenger RNA of NPAT was detected in all human tissues examined, and its genomic sequence was strongly conserved through eukaryotes, suggesting that the NPAT gene may be essential for cell maintenance and may be a member of the housekeeping genes. Analysis of the genomic region of NPAT surprisingly revealed that the gene existed only 0.5 kb apart from the 5' end of the ATM transcript with opposite transcriptional direction, it may be possible to propose the idea that the promoter region could be shared by both housekeeping genes and that each gene could influence the expression of the other.

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“…Protein kinase C (PKC), as first described by Nishizuka and colleagues, has been implicated in the control of many cellular processes (reviewed in [1,2]). It is now clear that the general properties used to define the enzyme are shared by a group of related proteins first identified through structural analysis [3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Unique substrate specificity and regulatory properties of PKC‐ε: a rationale for diversity

Schaap

Parker

Bristol³

et al. 1989

FEBS Letters

223

128

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PKC-e was isolated from a murine brain eDNA library. The clone, 261PKC-e, encoded a polypeptide of 737 amino acids that is homologous to other PKCs. Northern analysis showed that the 7 kb mRNA for this eDNA is widely expressed. The protein when expressed in COS-1 cells displayed phorbol ester-binding activity. However in order to detect the kinase activity of PKC-e, it was necessary to employ a synthetic peptide substrate based upon the pseudosubstrate site. Subsequent analysis demonstrated that PKC-e, while showing certain properties characteristic of the PKC family, has a quite distinct substrate specificity and is independent of Ca 2 +.

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Protein Kinase C and its Role in Cell Growth

Cited by 35 publications

References 826 publications

Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity.

Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity.

Identification and characterization of a new gene physically linked to the ATM gene.

Unique substrate specificity and regulatory properties of PKC‐ε: a rationale for diversity

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