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mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Kaushal Asrani1, Akshay Sood1, Alba Torres1

  • 1Department of Pathology and.

The Journal of Clinical Investigation
|September 26, 2017
PubMed

Insights

Loss of mTORC1 in the epidermis causes skin barrier defects and lethality by disrupting cell adhesion via ROCK signaling. Restoring ROCK signaling rescues these effects, revealing mTORC1

Area of Science:

  • Cell Biology
  • Dermatology
  • Molecular Biology

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) is crucial in cellular signaling.
  • Its role in epithelial development, particularly in vivo, remains incompletely understood.

Purpose of the Study:

  • To investigate the in vivo function of mTORC1 in epidermal development and barrier formation.
  • To elucidate the cellular consequences and signaling feedback mechanisms of mTORC1 loss in the skin.

Main Methods:

  • Conditional knockout mice lacking mTORC1 components (Rheb or Rptor) in the epidermis.
  • Analysis of skin barrier integrity, epidermal differentiation, and desmosomal protein expression.
  • Investigation of Rho kinase (ROCK) signaling pathways and TGF-β signaling.

Main Results:

  • Epidermal mTORC1 loss led to severe skin barrier defects, blistering, and early lethality.
  • This was associated with epidermal thinning, reduced desmosomal proteins, and impaired differentiation.
  • Constitutive activation of ROCK signaling was observed, causing increased cytoskeletal tension and poor cell adhesion.
  • Inhibition of ROCK1 rescued keratinocyte adhesion and differentiation.
  • mTORC1 loss induced feedback upregulation of TGF-β signaling, further activating ROCK.

Conclusions:

  • mTORC1 is essential for regulating epithelial barrier function, cytoskeletal tension, and cell-cell adhesion.
  • ROCK signaling is a key mediator of mTORC1's effects on epidermal integrity.
  • Complex feedback loops involving TGF-β signaling modulate mTORC1's impact on epithelial development.

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