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HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor

Colin D H Ratcliffe1,2, Nadeem Siddiqui1,2, Paula P Coelho1,2

  • 1Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

The Journal of Cell Biology
|November 9, 2018
PubMed

Insights

Microexon skipping in cytohesin-1 controls cell migration by altering how it binds to cell membranes. This splicing mechanism spatially restricts signaling, linking receptor tyrosine kinases to Arf6 activity in cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Alternative splicing, particularly microexon inclusion/skipping, is a key mechanism for generating protein diversity.
  • The functional roles of microexons and their impact on cellular signaling pathways remain largely unexplored.
  • Met receptor tyrosine kinase (RTK) signaling is crucial for regulating cell growth, invasion, and migration in both development and cancer.

Purpose of the Study:

  • To investigate the functional significance of microexon switching in cytohesin-1.
  • To elucidate the role of cytohesin-1 isoforms in Met-dependent cell migration.
  • To understand how microexon variations contribute to Arf6 signaling and phosphoinositide recognition.

Main Methods:

  • Analysis of cytohesin-1 isoforms generated by microexon inclusion/skipping.
  • Biochemical assays to determine phosphoinositide binding affinities (PI(4,5)P2 and PI(3,4,5)P3) of different cytohesin-1 variants.
  • Subcellular localization studies using microscopy to track isoform distribution within migrating cells.

Main Results:

  • Cytohesin-1 isoforms, differing by a three-nucleotide microexon, exhibit distinct affinities for PI(4,5)P2 (triglycine isoform) and PI(3,4,5)P3 (diglycine isoform).
  • The triglycine cytohesin-1 isoform preferentially localizes to the plasma membrane, while the diglycine isoform is enriched at the leading edge of migrating cells.
  • Microexon switching in cytohesin-1 directly influences Met-dependent cancer cell migration by modulating Arf6 activation.

Conclusions:

  • Microexon skipping in cytohesin-1 provides a mechanism for spatially regulating signaling pathways.
  • Differential phosphoinositide binding by cytohesin-1 isoforms dictates their subcellular localization and function.
  • This study establishes a mechanistic link between RTK signaling, phosphoinositide microdomains, and Arf6-mediated cell migration in cancer.

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