Major Substrate for Growth Factor-Activated Protein-Tyrosine Kinases Is a Low-Abundance Protein

Cooper, Jonathan A.; Hunter, Tony

doi:10.1128/mcb.5.11.3304-3309.1985

Molecular and Cellular Biology

1985

DOI: 10.1128/mcb.5.11.3304-3309.1985

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Major Substrate for Growth Factor-Activated Protein-Tyrosine Kinases Is a Low-Abundance Protein

Jonathan A. Cooper

Tony Hunter

Abstract: A scarce, soluble, conserved protein was identified as the nonphosphorylated precursor of two related 42-kilodalton phosphoproteins that contain phosphotyrosine in mitogen-stimulated but not control fibroblasts.

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1986

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Cited by 25 publications

References 29 publications

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Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.

Isacke¹,

Meisenhelder²,

Brown³

et al. 1986

The EMBO Journal

126

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Bombesin and the related mammalian peptides, such as gastrin‐releasing peptide (GRP), are potent mitogens for some fibroblast cell lines. Here we have examined the bombesin‐ and GRP‐mediated changes in the phosphorylation of proteins in Swiss 3T3 cells and compared these to the events observed after platelet‐derived growth factor (PDGF), epidermal growth factor (EGF) and tumor promoter treatment. In agreement with previous reports, bombesin, GRP and PDGF, but not EGF, increased the activity of protein kinase C. This was assayed by an inhibition of [125I]EGF binding, stimulation in phosphorylation of pp60c‐src on serine 12 and stimulation in phosphorylation of a group of 80 kd proteins. The different phosphorylated forms of the 80 kd proteins were examined by tryptic peptide mapping and shown to contain multiple phosphorylation sites. An investigation of the tyrosine phosphorylation events following mitogen treatment revealed a significant difference between PDGF and the bombesin peptides. PDGF treatment caused a marked increase in total cellular phosphotyrosine levels, and tyrosine phosphorylation both of known substrates and its own receptor. In contrast, bombesin and GRP treatments resulted in only a weak or undetectable increase in tyrosine phosphorylation of total cellular protein or known substrates. In this respect bombesin and GRP were more similar to EGF. The fact that the bombesin peptides do not induce a phosphorylation response identical with either PDGF or EGF suggests that there is not a single common signal pathway which is activated by all these mitogens.

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Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.

Isacke¹,

Meisenhelder²,

Brown³

et al. 1986

The EMBO Journal

126

View full text Add to dashboard Cite

show abstract

MAP kinase pathways: The first twenty years

Avruch

2007

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

249

171

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The MAP kinases, discovered approximately 20 years ago, together with their immediate upstream regulators, are among the most highly studied signal transduction molecules. This body of work has shaped many aspects of our present views of signal transduction by protein kinases. The effort expended in this area reflects the extensive participation of these regulatory modules in the control of cell fate decisions, i.e., proliferation, differentiation and death, across all eukaryotic phylla and in all tissues of metazoans. The discovery of these kinases is reviewed, followed by a discussion of some of the features of this signaling module that account for its broad impact on cell function and its enormous interest to many investigators.

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Mitogen-induced tyrosine phosphorylation of 41 kDa and 43 kDa proteins. Potential role in integrating multiple mitogenic signalling pathways

Kohno

Chatani

Tanaka

et al. 1992

Biochemical Journal

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We have examined the possible involvement of pertussis toxin (PT)-sensitive GTP-binding protein and protein kinase C (PKC) in mitogen-induced tyrosine phosphorylation of the 41 kDa and 43 kDa cytosol proteins using PT-pretreated (inactivation of PT-sensitive GTP-binding protein) or phorbol 12-myristate 13-acetate (PMA)-pretreated (depletion of PKC) mouse fibroblasts. The effects of the inactivation of PT-sensitive GTP-binding protein and the depletion of PKC on mitogen-stimulated tyrosine phosphorylation of the proteins were similar and varied significantly and systematically in response to growth factors. The important finding was that such inhibitory effects of PT-sensitive GTP-binding protein inactivation and PKC depletion on protein tyrosine phosphorylation induced by each mitogen always correlated well with their inhibitory effects on each mitogen-stimulated DNA synthesis. Although the extent of platelet-derived-growth-factor-induced phosphorylation of the proteins was decreased to approx. 50% in PT- and PMA-pretreated cells compared with native cells, protein phosphorylation itself was not affected and occurred at identical sites on each protein in native, PT- and PMA-pretreated cells. These results suggest that: (1) 41 kDa and 43 kDa proteins are located downstream of PT-sensitive GTP-binding protein and PKC in the mitogenic signalling pathways of growth factors, (2) protein phosphorylation occurs via a cascade of events which includes the activation of the receptor tyrosine kinases, PKC and other unidentified kinase(s) which directly participate(s) in the phosphorylation of the 41 kDa and 43 kDa proteins, and (3) their phosphorylation may play an important role in integrating multiple mitogenic signalling pathways.

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Major Substrate for Growth Factor-Activated Protein-Tyrosine Kinases Is a Low-Abundance Protein

Abstract: A scarce, soluble, conserved protein was identified as the nonphosphorylated precursor of two related 42-kilodalton phosphoproteins that contain phosphotyrosine in mitogen-stimulated but not control fibroblasts.

Cited by 25 publications

References 29 publications

Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.

Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.

MAP kinase pathways: The first twenty years

Mitogen-induced tyrosine phosphorylation of 41 kDa and 43 kDa proteins. Potential role in integrating multiple mitogenic signalling pathways

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