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Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent,

D Fambrough1, K McClure, A Kazlauskas

  • 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

Cell
|June 25, 1999
PubMed

Insights

Receptor tyrosine kinase (RTK) pathways broadly overlap in inducing immediate early genes (IEGs). Specific pathway mutations reveal distinct gene induction patterns, impacting cellular responses.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Expression Analysis

Background:

  • Receptor tyrosine kinases (RTKs) are crucial cell surface receptors that regulate diverse cellular processes through downstream signaling pathways.
  • Immediate early genes (IEGs) are rapidly and transiently activated genes that play key roles in cellular responses to external stimuli.
  • Understanding the interplay between RTK signaling and IEG induction is vital for deciphering cellular plasticity and response mechanisms.

Purpose of the Study:

  • To investigate the relationship between activated receptor tyrosine kinase (RTK) signaling pathways and the transcriptional induction of immediate early genes (IEGs).
  • To identify specific RTK-activated pathways responsible for the induction of fibroblast IEGs.
  • To compare the IEG induction profiles of different RTKs in fibroblasts.

Main Methods:

  • Global gene expression monitoring using transcriptomic analysis.
  • Utilizing mutant platelet-derived growth factor beta receptor (PDGFRbeta) constructs lacking specific signaling pathway binding sites (PLCgamma, PI3K, SHP2, RasGAP, Grb2).
  • Comparative analysis of IEG induction by PDGFRbeta and fibroblast growth factor receptor 1 (FGFR1).

Main Results:

  • Identified 66 fibroblast IEGs induced by PDGFRbeta signaling.
  • Mutant PDGFRbeta receptors lacking PLCgamma, PI3K, SHP2, and RasGAP binding sites retained partial ability to induce 64 of these IEGs, indicating overlapping pathway effects.
  • Removal of the Grb2-binding site significantly reduced IEG induction, highlighting its broad importance.
  • A PDGFRbeta mutant restoring the RasGAP-binding site induced a distinct set of interferon-responsive genes.
  • PDGFRbeta and FGFR1 induced essentially identical IEGs in fibroblasts.

Conclusions:

  • Multiple RTK-activated signaling pathways exert broadly overlapping effects on IEG induction.
  • Specific signaling components within RTK pathways contribute to the induction of distinct gene sets, influencing cellular responses.
  • PDGFRbeta and FGFR1 signaling pathways converge on the induction of a similar set of immediate early genes in fibroblasts.

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