Abstract
EphA2 receptor tyrosine kinase is activated by ephrin-A1 ligand, which harbors a glycosylphosphatidylinositol anchor that enhances lipid raft localization. Although EphA2 and ephrin-A1 modulate keratinocyte migration and differentiation, the ability of this cell-cell communication complex to localize to different membrane regions in keratinocytes remains unknown. Using a combination of biochemical and imaging approaches, we provide evidence that ephrin-A1 and a ligand-activated form of EphA2 partition outside of lipid raft domains in response to calcium-mediated cell-cell contact stabilization in normal human epidermal keratinocytes. EphA2 transmembrane domain swapping with a shorter and molecularly distinct transmembrane domain of EphA1 resulted in decreased localization of this receptor tyrosine kinase at cell-cell junctions and increased expression of ephrin-A1, which is a negative regulator of keratinocyte migration. Accordingly, altered EphA2 membrane distribution at cell-cell contacts limited the ability of keratinocytes to seal linear scratch wounds in vitro in an ephrin-A1–dependent manner. Collectively, these studies highlight a key role for the EphA2 transmembrane domain in receptor-ligand membrane distribution at cell-cell contacts that modulates ephrin-A1 levels to allow for efficient keratinocyte migration with relevance for cutaneous wound healing.
Original language | English (US) |
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Pages (from-to) | 2133-2143 |
Number of pages | 11 |
Journal | Journal of Investigative Dermatology |
Volume | 138 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2018 |
Funding
This work was supported by the National Institutes of Health (AR062110 [to SG]; EY06769, EY017539, EY019463 [to RML]), Cellular and Molecular Basis of Disease training fellowship (T32-GM08061 [to RV]), Cancer Smashers Foundation Award (to RV), Research Career Development Award from the Dermatology Foundation (to BPW), and a Skin Disease Research Center grant (P30-AR057216-01]).
ASJC Scopus subject areas
- Dermatology
- Molecular Biology
- Biochemistry
- Cell Biology