Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors: Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling

Sheela R Kadapakkam, Fang Wang, Elena Fuior, Alvin Berger, Jie Wu, Thomas W. Sturgill, Dana Beitner-Johnson, Derek LeRoith, Lyuba Varticovski, Sarah Spiegel

Research output: Contribution to journalArticle

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Abstract

Platelet-derived growth factor (PDGF) and serum, but not epidermal growth factor (EGF), stimulated sphingosine kinase activity in Swiss 3T3 fibroblasts and increased intracellular concentrations of sphingosine 1- phosphate (SPP), a sphingolipid second messenger (Olivera, A., and Spiegel, S. (1993) Nature 365, 557-560). We report herein that DL-threo- dihydrosphingosine (DHS), a competitive inhibitor of sphingosine kinase that prevents PDGF-induced SPP formation, specifically inhibited the activation of two cyclin-dependent kinases (p34(cdc2) kinase and Cdk2 kinase) induced by PDGF, but not by EGF. SPP reversed the inhibitory effects of DHS on PDGF- stimulated cyclin-dependent kinases and DNA synthesis, demonstrating that the DHS effects were mediated via inhibition of sphingosine kinase. DHS also markedly reduced PDGF-stimulated but not EGF-stimulated mitogen-activated protein kinase activity and DNA binding activity of activator protein-1. Examination of the early signaling events of PDGF action revealed that DHS did not affect PDGF-induced autophosphorylation of the growth factor receptor or phosphorylation of the SH2/SH3 adaptor protein Shc and its association with Grb2. This sphingosine kinase inhibitor did not abrogate activation of phosphatidylinositol 3-kinase by PDGF. In agreement, treatment with SPP had no effect on these responses but did, however, potently stimulate phosphorylation of Crk, another SH2/SH3 adaptor protein. Moreover, DHS inhibited PDGF-stimulated, but not EGF-stimulated, Crk phosphorylation. Thus, regulation of sphingosine kinase activity defines divergence in signal transduction pathways of PDGF and EGF receptors leading to mitogen-activated protein kinase activation.

Original languageEnglish (US)
Pages (from-to)10777-10783
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number16
DOIs
StatePublished - Apr 18 1997
Externally publishedYes

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Signal transduction
Platelet-Derived Growth Factor
Epidermal Growth Factor
Signal Transduction
Phosphorylation
Cyclin-Dependent Kinases
Chemical activation
Mitogen-Activated Protein Kinases
Shc Signaling Adaptor Proteins
Phosphotransferases
ErbB Receptors
sphingosine 1-phosphate
Phosphatidylinositol 3-Kinase
Sphingolipids
Growth Factor Receptors
DNA
Transcription Factor AP-1
Second Messenger Systems
Fibroblasts
safingol

ASJC Scopus subject areas

  • Biochemistry

Cite this

Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors : Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. / Kadapakkam, Sheela R; Wang, Fang; Fuior, Elena; Berger, Alvin; Wu, Jie; Sturgill, Thomas W.; Beitner-Johnson, Dana; LeRoith, Derek; Varticovski, Lyuba; Spiegel, Sarah.

In: Journal of Biological Chemistry, Vol. 272, No. 16, 18.04.1997, p. 10777-10783.

Research output: Contribution to journalArticle

Kadapakkam, Sheela R ; Wang, Fang ; Fuior, Elena ; Berger, Alvin ; Wu, Jie ; Sturgill, Thomas W. ; Beitner-Johnson, Dana ; LeRoith, Derek ; Varticovski, Lyuba ; Spiegel, Sarah. / Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors : Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 16. pp. 10777-10783.
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abstract = "Platelet-derived growth factor (PDGF) and serum, but not epidermal growth factor (EGF), stimulated sphingosine kinase activity in Swiss 3T3 fibroblasts and increased intracellular concentrations of sphingosine 1- phosphate (SPP), a sphingolipid second messenger (Olivera, A., and Spiegel, S. (1993) Nature 365, 557-560). We report herein that DL-threo- dihydrosphingosine (DHS), a competitive inhibitor of sphingosine kinase that prevents PDGF-induced SPP formation, specifically inhibited the activation of two cyclin-dependent kinases (p34(cdc2) kinase and Cdk2 kinase) induced by PDGF, but not by EGF. SPP reversed the inhibitory effects of DHS on PDGF- stimulated cyclin-dependent kinases and DNA synthesis, demonstrating that the DHS effects were mediated via inhibition of sphingosine kinase. DHS also markedly reduced PDGF-stimulated but not EGF-stimulated mitogen-activated protein kinase activity and DNA binding activity of activator protein-1. Examination of the early signaling events of PDGF action revealed that DHS did not affect PDGF-induced autophosphorylation of the growth factor receptor or phosphorylation of the SH2/SH3 adaptor protein Shc and its association with Grb2. This sphingosine kinase inhibitor did not abrogate activation of phosphatidylinositol 3-kinase by PDGF. In agreement, treatment with SPP had no effect on these responses but did, however, potently stimulate phosphorylation of Crk, another SH2/SH3 adaptor protein. Moreover, DHS inhibited PDGF-stimulated, but not EGF-stimulated, Crk phosphorylation. Thus, regulation of sphingosine kinase activity defines divergence in signal transduction pathways of PDGF and EGF receptors leading to mitogen-activated protein kinase activation.",
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T2 - Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling

AU - Kadapakkam, Sheela R

AU - Wang, Fang

AU - Fuior, Elena

AU - Berger, Alvin

AU - Wu, Jie

AU - Sturgill, Thomas W.

AU - Beitner-Johnson, Dana

AU - LeRoith, Derek

AU - Varticovski, Lyuba

AU - Spiegel, Sarah

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AB - Platelet-derived growth factor (PDGF) and serum, but not epidermal growth factor (EGF), stimulated sphingosine kinase activity in Swiss 3T3 fibroblasts and increased intracellular concentrations of sphingosine 1- phosphate (SPP), a sphingolipid second messenger (Olivera, A., and Spiegel, S. (1993) Nature 365, 557-560). We report herein that DL-threo- dihydrosphingosine (DHS), a competitive inhibitor of sphingosine kinase that prevents PDGF-induced SPP formation, specifically inhibited the activation of two cyclin-dependent kinases (p34(cdc2) kinase and Cdk2 kinase) induced by PDGF, but not by EGF. SPP reversed the inhibitory effects of DHS on PDGF- stimulated cyclin-dependent kinases and DNA synthesis, demonstrating that the DHS effects were mediated via inhibition of sphingosine kinase. DHS also markedly reduced PDGF-stimulated but not EGF-stimulated mitogen-activated protein kinase activity and DNA binding activity of activator protein-1. Examination of the early signaling events of PDGF action revealed that DHS did not affect PDGF-induced autophosphorylation of the growth factor receptor or phosphorylation of the SH2/SH3 adaptor protein Shc and its association with Grb2. This sphingosine kinase inhibitor did not abrogate activation of phosphatidylinositol 3-kinase by PDGF. In agreement, treatment with SPP had no effect on these responses but did, however, potently stimulate phosphorylation of Crk, another SH2/SH3 adaptor protein. Moreover, DHS inhibited PDGF-stimulated, but not EGF-stimulated, Crk phosphorylation. Thus, regulation of sphingosine kinase activity defines divergence in signal transduction pathways of PDGF and EGF receptors leading to mitogen-activated protein kinase activation.

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