Ligand-independent activation of platelet-derived growth factor receptor is a necessary intermediate in lysophosphatidic, acid-stimulated mitogenic activity in L cells

Andreas Herrlich, Henrik Daub, Axel Knebel, Peter Herrlich, Axel Ullrich, Günter Schultz, Thomas Gudermann

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

Growth factor-derived mitogenic signals from the cell surface are transmitted to the nucleus via receptor tyrosine kinases (RTKs), the adaptor proteins Shc and Grb2, and a Ras-dependent protein kinase cascade that activates the extracellular signal regulated kinase (ERK) subfamily of mitogen-activated protein kinases. ERKs also are activated by hormones that stimulate G protein-coupled receptors (GPCRs). We report here that, in agreement with previous data, the epidermal growth factor receptor (EGFR) is a signaling intermediate in ERK activation by GPCRs. Of import, we show that cross-talk between two classes of surface receptors, RTKs and GPCRs, is a general feature. Lysophosphatidic acid not only induces ligand-independent tyrosine autophosphorylation of EGFR but also of platelet-derived growth factor β receptor (PDGF-β-R) as shown by detection of tyrosine phosphorylation and by the use of specific inhibitors of RTKs. The cross- talk appears to be cell type-specific: In L cells that lack EGFR, lysophosphatidic acid-induced Shc and ERK activation is prevented completely by specific inhibition of PDGFR, whereas in COS-7 cells expressing only EGFR, the pathway via EGFR is chosen. In Rat-1 cells, however, that express both EGFR and PDGFR, the EGFR pathway dominates.

Original languageEnglish
Pages (from-to)8985-8990
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number15
DOIs
StatePublished - Jul 21 1998

Keywords

  • Cross-talk
  • Epidermal growth factor receptor
  • G protein-coupled receptors
  • MAP kinase

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