Membrane-bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche

FASEB J. 2012 Sep;26(9):3738-53. doi: 10.1096/fj.12-206045. Epub 2012 May 25.


Morphogenesis, as illustrated by melanocyte migration and homing to the skin, requires cadherin adhesion, integrin-dependent migration and Kit-ligand growth factor signaling. However, it is not known how Kit ligand regulates integrin or cadherin-dependent intraepidermal melanocyte behavior. To answer this question, we developed specific 2-dimensional (2D) and 3D culture systems analyzing how soluble or immobilized Kit-ligand-regulated melanocyte migration on vitronectin and laminin, or within a monolayer of kidney epithelial cells. In a 2D system, soluble Kit ligand stimulated integrin-dependent melanoblast migration and chemotaxis and accelerated integrin turnover. In contrast, immobilized, but not soluble, Kit ligand, enhanced integrin-dependent melanocyte spreading on suboptimal laminin concentrations. In 3D, membrane-bound Kit ligand induced intraepithelial melanocyte proliferation, survival, and tight adhesion to epithelial cells, while cleavable Kit ligand was less effective. In contrast, melanocyte motility was independent of membrane-bound Kit ligand, but increased in the presence of the cleavable Kit-ligand isoform. Transmembrane-dimerization or basolateral-targeting mutants of Kit ligand altered intraepithelial melanocyte localization, survival, and adhesion to epithelial cells. These data and the identification of c-kit/Kit-ligand clusters at cell contacts suggest that membrane-bound Kit ligand captures cell surface-expressed c-kit, providing mechanical anchoring and survival signaling within intraepithelial niches, and thereby defining a new mechanism for melanocyte homeostasis and requirement for environmental niches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Adhesion / physiology*
  • Cell Survival / physiology*
  • Coculture Techniques
  • Culture Media, Conditioned
  • Dogs
  • Epithelial Cells / cytology*
  • Flow Cytometry
  • Madin Darby Canine Kidney Cells
  • Melanocytes / cytology*
  • Mice
  • Molecular Sequence Data
  • Stem Cell Factor / physiology*


  • Culture Media, Conditioned
  • Stem Cell Factor