CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

J Exp Med. 2013 Jan 14;210(1):173-90. doi: 10.1084/jem.20121651. Epub 2013 Jan 7.


Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal β1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • CSK Tyrosine-Protein Kinase
  • Cell Adhesion / genetics
  • Cell Movement / genetics
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Epidermis / metabolism
  • Epidermis / pathology
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Fusion Regulatory Protein 1, Heavy Chain / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Hair Follicle / metabolism
  • Homeostasis
  • Integrins / metabolism
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Mice
  • Mice, Transgenic
  • Reactive Oxygen Species / metabolism
  • Rho Guanine Nucleotide Exchange Factors
  • Signal Transduction
  • Skin / metabolism*
  • Skin Physiological Phenomena
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transcription Factors / metabolism
  • Wound Healing / physiology*
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein
  • src-Family Kinases / metabolism


  • Arhgef12 protein, mouse
  • DNA-Binding Proteins
  • Fusion Regulatory Protein 1, Heavy Chain
  • GLUT4 enhancer factor, mouse
  • Guanine Nucleotide Exchange Factors
  • Integrins
  • Reactive Oxygen Species
  • Rho Guanine Nucleotide Exchange Factors
  • Slc3A2 protein, mouse
  • Transcription Factors
  • Tamoxifen
  • afimoxifene
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein