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Mechanism of kinase activation in the receptor for colony-stimulating factor 1

A W Lee1, A W Nienhuis

  • 1Clinical Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

Proceedings of the National Academy of Sciences of the United States of America
|September 1, 1990
PubMed

Insights

Receptor tyrosine kinase activation occurs through ligand-induced oligomerization, not intramolecular conformational changes. This study demonstrates that receptor dimerization is key for signaling pathways, impacting cell proliferation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Receptor tyrosine kinases (RTKs) are crucial cell surface proteins that regulate vital cellular processes.
  • RTK activation mechanisms are debated, with intramolecular and intermolecular models proposed.
  • Understanding RTK activation is key to deciphering signaling pathways and disease mechanisms.

Purpose of the Study:

  • To investigate the mechanism of receptor tyrosine kinase activation.
  • To differentiate between intramolecular and intermolecular models of kinase activation.
  • To elucidate the role of ligand-induced receptor oligomerization in RTK signaling.

Main Methods:

  • Site-directed mutagenesis of colony-stimulating factor 1 receptor (CSF-1R) cDNA to introduce large insertions.
  • Expression of mutant CSF-1R on the cell surface for ligand binding and signaling assays.
  • Construction and analysis of a hybrid receptor combining glycophorin A extracellular domain with CSF-1R transmembrane and cytoplasmic domains.

Main Results:

  • Mutant CSF-1R receptors with insertions maintained high-affinity ligand binding and exhibited ligand-stimulated autophosphorylation.
  • These mutant receptors successfully signaled mitogenesis and cellular proliferation upon ligand stimulation.
  • A hybrid receptor demonstrated antibody-induced kinase activity, supporting the intermolecular model.

Conclusions:

  • The findings strongly support a mechanism of RTK activation driven by ligand-induced receptor oligomerization.
  • Receptor dimerization, rather than transmembrane conformational changes, is the primary mode of activation.
  • This clarifies a fundamental aspect of cell signaling and kinase function.

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