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Plasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth

P M Comoglio1, L Tamagnone, C Boccaccio

  • 1Institute for Cancer Research and Treatment, University of Turin School of Medicine, Candiolo, 10060, Italy. pcomoglio@ircc.unito.it

Experimental Cell Research
|December 2, 1999
PubMed

Insights

Plasminogen-related growth factors (PRGFs) drive invasive growth by coordinating cell proliferation, survival, motility, and polarity. Aberrant activation of PRGF or semaphorin pathways promotes cancer cell invasion and metastasis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Plasminogen-related growth factors (PRGFs), or scatter factors, initiate invasive growth by integrating cell proliferation, survival, motility, and polarity.
  • This process, crucial for epithelial organ development (branching morphogenesis), involves PRGF receptors, tyrosine kinases MET and RON, which possess unique signaling capabilities.
  • These receptors bind SH2-containing signal transducers via a dual-tyrosine docking site, activating pathways like Ras, phosphatidylinositol 3-kinase, and STAT, which mediate growth, scattering, and morphogenesis.

Purpose of the Study:

  • To explore the molecular mechanisms underlying invasive growth driven by PRGFs.
  • To investigate the role of newly identified sex/plexin proteins, homologous to Met, in cell signaling and invasive processes.
  • To understand how deregulation of PRGF and semaphorin pathways contributes to cancer cell invasiveness and metastasis.

Main Methods:

  • Analysis of genetic programs controlling cell proliferation, survival, motility, and polarity.
  • Characterization of PRGF receptor tyrosine kinases (MET, RON) and their signaling pathways.
  • Identification and homology analysis of the novel human gene family encoding sex/plexins and their interaction with semaphorins.

Main Results:

  • PRGFs orchestrate a program of invasive growth essential for physiological branching morphogenesis.
  • MET and RON receptors utilize a multifunctional docking site to activate Ras, PI3K, and STAT pathways.
  • The newly identified sex/plexin family, receptors for semaphorins, show homology to Met and are implicated in processes resembling scattering and invasive growth.
  • Mutations or overexpression of PRGF or semaphorin pathway components confer invasive and metastatic properties to cancer cells.

Conclusions:

  • PRGFs and semaphorin signaling pathways are critical regulators of cell behavior, influencing both normal development and cancer progression.
  • Dysregulation of these pathways, through genetic alterations or overexpression, is a key mechanism driving cancer cell invasion and metastasis.
  • The identification of sex/plexins expands our understanding of receptor tyrosine kinase signaling in cell adhesion, migration, and tissue architecture.

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