Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor

Ek, Bo; Westermark, Bengt; Wasteson, Åke; Heldin, Carl‐Henrik

doi:10.1038/295419a0

Cited by 683 publications

(214 citation statements)

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“…4), one in which both kinases serve separate cellular functions, and another one with sequential activation of the kinases . The first model implies that the tyrosine-specific enzyme activity is involved in insulin's growth-promoting action similar to the tyrosine phosphorylations mediating the cellular responses to growth factors such as EGF (Cohen et al, 1980), PDGF (Ek et al, 1982) and TGF-a (Reynolds et al, 1981) and several cellular and retroviral oncogene proteins (Hunter, 1982(Hunter, , 1984Bishop, 1983;Heldin & Westermark, 1984). In contrast, the serine kinase would play a role in insulin's metabolic actions.…”

Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

confidence: 99%

“…This novel observation is of interest for our understanding of insulin-regulated processes, since it is now recognized that covalent phosphorylation-dephosphorylation of proteins is a mechanism whereby many cellular functions are regulated by hormones and neurotransmitters (Denton et al, 1981;Cohen, 1982;Houslay, 1981). Furthermore, protein kinases are also constituents of receptors for several polypeptide growth factors, including epidermal growth factor (EGF) (Cohen et al, 1980), platelet-derived growth factor (PDGF) (Ek et al, 1982), transforming growth factor (TGF-a) (Reynolds et al, 1981), and insulin-like growth factor I (IGF-I) (Jacobs et al, 1983, implying that receptor kinase activity may represent a general mechanism in transmembrane signalling of hormones and growth factors. The purpose of the present Review is to describe the current status of functional and structural properties of insulin receptors in vertebrates.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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The insulin receptor is an integral membrane glycoprotein (Mr approximately 300,000) composed of two alpha-subunits (Mr approximately 130,000) and two beta-subunits (Mr approximately 95,000) linked by disulphide bonds. This oligomeric structure divides the receptor into two functional domains such that alpha-subunits bind insulin and beta-subunits possess tyrosine kinase activity. The amino acid sequence deduced from cDNA of the single polypeptide chain precursor of human placental insulin receptor revealed that alpha- and beta-subunits consist of 735 and 620 residues, respectively. The alpha-subunit is hydrophilic, disulphide-bonded, glycosylated and probably extracellular. The beta-subunit consists of a short extracellular region which links the alpha-subunit through disulphide bridges, a hydrophobic transmembrane region and a longer cytoplasmic region which is structurally homologous with other tyrosine kinases like the src oncogene product and EGF receptor kinases. The cellular function of insulin receptors is dual: transmembrane signalling and endocytosis of hormone. The binding of insulin to its receptor on the cell membrane induces transfer of signal from extracellular to cytoplasmic receptor domains leading to activation of cell metabolism and growth. In addition, hormone-receptor complexes are internalized leading to intracellular proteolysis of insulin, whereas receptors are recycled to the membrane. These phenomena are kinetically well-characterized, but their molecular mechanisms remain obscure. Insulin receptor in different tissues and animal species are homologous in their structure and function, but show also significant differences regarding size of alpha-subunits, binding kinetics, insulin specificity and receptor-mediated degradation. We suggest that this heterogeneity of receptors may be linked to the diversity in insulin effects on metabolism and growth in various cell types. The purified insulin receptor phosphorylates its own beta-subunit and exogenous protein and peptide substrates on tyrosine residues, a reaction which is insulin-sensitive, Mn2+-dependent and specific for ATP. Tyrosine phosphorylation of the beta-subunit activates receptor kinase activity, and dephosphorylation with alkaline phosphatase deactivates the kinase. In intact cells or impure receptor preparations, a serine kinase is also activated by insulin. The cellular role of two kinase activities associated with the insulin receptor is not known, but we propose that the tyrosine- and serine-specific kinases mediate insulin actions on metabolism and growth either through dual-signalling or sequential pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

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“…Parallel observations on phosphorylation of tyrosine residues have been made with the platelet-derived growth factor [68,69] and insulin [65] receptors. In the case of EGF, there is some evidence that stimulation of tyrosine phosphorylation could not be sufficient for mitogenesis.…”

Section: Discussionmentioning

confidence: 86%

Characterization of the epidermal‐growth‐factor‐dependent phosphorylation system from normal mouse‐liver sinusoidal plasma membranes

Ehrhart

Rollet

Komano

et al. 1983

European Journal of Biochemistry

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Blood sinusoidal plasma membrane subfractions were isolated from normal mouse liver in the presence of the proteinase inhibitors PhMeSO2F and iodoacetamide. They were purified from smooth microsomal and Golgi vesicle contaminants. The phosphorylation reaction was studied at 33°C, in the presence of 2 mM MnCl2. Addition of epidermal growth factor (EGF) to the preparations stimulated 32P incorporation from [γ‐32P]ATP or [γ‐32P]GTP essentially into one 170000 Mr protein. Some incorporation was observed in a minor 120000‐Mr component which appears to be a degradation product of the 170000‐Mr component. No EGF‐dependent phosphorylation of other membrane proteins or various exogenous proteins could be detected in vitro. The dephosphorylation of the 170000‐Mr component was observed after 4 min of incubation at 33°C. This dephosphorylation reaction was inhibited by addition of 5 mM p‐nitrophenyl phosphate but not by addition of micromolar Zn2+, Be2+ or orthovanadate. The 170000‐Mr protein specifically bound 125I‐labeled EGF and thus appeared to be the hepatic EGF receptor. The EGF stimulatable kinase activity considerably enhances incorporation of 32P into tyrosine residues of the 170000‐Mr EGF receptor at 33°C. Tryptic peptide maps of the 32P‐labeled 170000‐Mr protein revealed a multiplicity of phosphorylated sites. Seven 32P‐labeled phosphopeptides were observed after EGF stimulation, three of them being largely prominent. Tryptic peptide maps of the 170000‐Mr protein after it was covalently linked to 125I‐labeled EGF showed only one 125I‐labeled peptide, the migration of which appeared different from that of 32P‐labeled phosphopeptides. These findings were confirmed by V8 protease unidimensional peptide mapping of the 170000‐Mr protein, labeled with 32P or 125I‐EGF.

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“…Furthermore, tyrosine-specific protein kinase activity has been associated with the actions of several hormones and growth factors including insulin [2], epidermal growth factor (EGF) [3] and platelet-derived growth factor [4]. A number of cellular substrates for the viral tyrosine protein kinases have been identified (see [5] for review).…”

mentioning

confidence: 99%

“…Poly(aspartic ' acid) and poly(g1utamic acid) had only weak effects on peptide tyrosine phosphorylation. The results support the concept that acidic residues and not basic residues are important specificity determinants for the epidermal-growthfactor-stimulated tyrosine protein kinase.Tyrosine phosphorylation is now recognized as an important regulatory mechanism in the transformation of host cells by a group of RNA tumor viruses [I].Furthermore, tyrosine-specific protein kinase activity has been associated with the actions of several hormones and growth factors including insulin [2], epidermal growth factor (EGF) [3] and platelet-derived growth factor [4]. A number of cellular substrates for the viral tyrosine protein kinases have been identified (see [5] for review).…”

mentioning

confidence: 99%

Synthetic peptide substrates for the membrane tyrosine protein kinase stimulated by epidermal growth factor

1984

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The substrate specificity of the epidermal-growth-factor-stimulated tyrosine protein kinase of A431 cell membranes has been studied using a series of synthetic peptide analogs of the sequence around the phosphorylated tyrosine-41 9 of pp60"'". The nine-residue peptide Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Thr-Ala was phosphorylated on tyrosine with an apparent K, of 0.4mM and a V' of 5.7nmol xmin-' xmg-'. Synthetic peptide tyrosine phosphorylation was stimulated by epidermal growth factor but not by insulin or relaxin. Extension of the nineresidue peptide to include the basic residues, arginine-412, arginine-422 and lysine-423 led to an increased apparent K,. Substitution of glutamic-418 by leucine also increased the apparent K,. In the model peptide Ile-Xaa-Xaa-AlaAla-Tyr-Thr-Ala a lower apparent K, was obtained when Xaa was glutamic rather than aspartic acid. Poly(aspartic ' acid) and poly(g1utamic acid) had only weak effects on peptide tyrosine phosphorylation. The results support the concept that acidic residues and not basic residues are important specificity determinants for the epidermal-growthfactor-stimulated tyrosine protein kinase.Tyrosine phosphorylation is now recognized as an important regulatory mechanism in the transformation of host cells by a group of RNA tumor viruses [I].Furthermore, tyrosine-specific protein kinase activity has been associated with the actions of several hormones and growth factors including insulin [2], epidermal growth factor (EGF) [3] and platelet-derived growth factor [4]. A number of cellular substrates for the viral tyrosine protein kinases have been identified (see [5] for review). Since the tyrosine protein kinases appear to be an important class of regulatory enzymes the molecular basis of their protein substrate specificity is of considerable interest. From the results of sequence studies [6 -91 it has been proposed that acidic residues on the NH2-terminal side of the phosphorylation site are important specificity determinants for the viral tyrosine protein kinase. The presence of more distant basic residues in this region has also been noted [7]. Recently the substrate specificity of tyrosine protein kinase has been examined using synthetic peptides in several laboratories [I0 -121. Hunter [lo] reported that the Y73 tyrosine protein kinase phosphorylated synthetic peptides corresponding to the region around tyrosine-419 in pp60"" [8]. In this peptide glutamic-415 had an influence on the kinetics of peptide phosphorylation. Similar observations have been made with the EGF-stimulated tyrosine protein kinase of A431 cell membranes where Pike et al. [ l l ] found that both aspartic-416 and glutamic-415 had modest effects on the kinetics of peptide phosphorylation. Further support for the concept that acidic residues may be important specificity determinants for tyrosine protein kinases comes from studies in which it was found that certain peptide hormones containing acidic residues and tyrosine were also substrates for these enzymes [I 2,131.The purpose of the present study wa...

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Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor

Cited by 683 publications

References 32 publications

Protein kinase activity of the insulin receptor

Protein kinase activity of the insulin receptor

Characterization of the epidermal‐growth‐factor‐dependent phosphorylation system from normal mouse‐liver sinusoidal plasma membranes

Synthetic peptide substrates for the membrane tyrosine protein kinase stimulated by epidermal growth factor

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