Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1.
EphA2 is a receptor tyrosine kinase that is engaged and activated by membrane-linked ephrin-A ligands residing on adjacent cell surfaces. Ligand targeting of EphA2 has been implicated in epithelial growth regulation by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2)-mitogen activated protein kinase (MAPK) pathway. Although contact-dependent EphA2 activation was required for dampening Erk1/2-MAPK signaling after a calcium switch in primary human epidermal keratinocytes, the loss of this receptor did not prevent exit from the cell cycle. Incubating keratinocytes with a soluble ephrin-A1-Fc peptide mimetic to target EphA2 further increased receptor activation leading to its down-regulation. Moreover, soluble ligand targeting of EphA2 restricted the lateral expansion of epidermal cell colonies without limiting proliferation in these primary cultures. Rather, ephrin-A1-Fc peptide treatment promoted epidermal cell colony compaction and stratification in a manner that was associated with increased keratinocyte differentiation. The ligand-dependent increase in keratinocyte adhesion and differentiation relied largely upon the up-regulation of desmoglein 1, a desmosomal cadherin that maintains the integrity and differentiated state of suprabasal keratinocytes in the epidermis. These data suggest that keratinocytes expressing EphA2 in the basal layer may respond to ephrin-A1-based cues from their neighbors to facilitate entry into a terminal differentiation pathway.
Lin
Samantha
S
Department of Dermatology and Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Gordon
Kristin
K
Kaplan
Nihal
N
Getsios
Spiro
S
D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion; D002450:Cell Communication; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051183:Desmoglein 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D036382:Ephrin-A1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000494:pharmacology; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*
D051183:Desmoglein 1; D036382:Ephrin-A1; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D036104:Receptor, EphA2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium