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Src family kinases inhibit differentiation of intestinal epithelial cells through the Hippo effector YAP1

Sepideh Fallah1, Jean-François Beaulieu1

  • 1Laboratory of Intestinal Physiopathology, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de recherche du Centre hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.

Biology Open
|October 25, 2021
PubMed

Insights

Src family kinases (SFKs) regulate YAP1, a Hippo pathway effector, controlling intestinal cell differentiation. Inhibiting SFKs reduces YAP1, promoting absorptive and goblet cell development.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Molecular Biology

Background:

  • Intestinal epithelial cell differentiation is crucial for gut function.
  • YAP1, a Hippo pathway effector, inhibits absorptive and goblet cell differentiation.
  • The regulation of YAP1 in intestinal cells remains incompletely understood.

Purpose of the Study:

  • To investigate the role of Src family kinases (SFKs) in regulating YAP1.
  • To determine the impact of SFK inhibition on intestinal cell differentiation.
  • To explore the distinct roles of YAP1 and its paralog TAZ in intestinal cell function.

Main Methods:

  • Utilized shRNA knockdown and SFK inhibition in intestinal cell models (Caco-2/15).
  • Assessed YAP1 protein levels and expression of differentiation markers (CDX2, HNF4α).
  • Performed specific knockdown of YAP1 and TAZ to evaluate their individual contributions.

Main Results:

  • SFK inhibition significantly reduced YAP1 protein levels.
  • Inhibition of SFKs increased CDX2, HNF4α (P1 form), and markers of absorptive and goblet cell differentiation.
  • TAZ levels were unaffected by SFK inhibition, and TAZ knockdown impaired absorptive cell differentiation, suggesting non-interchangeable roles with YAP1.

Conclusions:

  • SFKs are key regulators of YAP1 activity in intestinal epithelial cells.
  • Targeting SFKs promotes intestinal cell differentiation by modulating YAP1.
  • YAP1 and TAZ have distinct, non-interchangeable functions in regulating intestinal cell fate and differentiation.
Keywords:
CDX2DifferentiationHNF1HNF4Intestinal cellSrc family kinasesTAZYAP1

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