Mechanisms of plakoglobin-dependent adhesion: desmosome-specific functions in assembly and regulation by epidermal growth factor receptor.
Plakoglobin (PG) is a member of the Armadillo family of adhesion/signaling proteins that can be incorporated into both adherens junctions and desmosomes. Loss of PG results in defects in the mechanical integrity of heart and skin and decreased adhesive strength in keratinocyte cultures established from the skin of PG knock-out (PG-/-) mice, the latter of which cannot be compensated for by overexpressing the closely related beta-catenin. In this study, we examined the mechanisms of PG-regulated adhesion in murine keratinocytes. Biochemical and morphological analyses indicated that junctional incorporation of desmosomal, but not adherens junction, components was impaired in PG-/- cells compared with PG+/- controls. Re-expression of PG, but not beta-catenin, in PG-/- cells largely reversed these effects, indicating a key role for PG in desmosome assembly. Epidermal growth factor (EGF) receptor activation resulted in Tyr phosphorylation of PG, which was accompanied by a loss of desmoplakin from desmosomes and decreased adhesive strength following 18-h EGF treatment. Importantly, introduction of a phosphorylation-deficient PG mutant into PG null cells prevented the EGF receptor-dependent loss of desmoplakin from junctions, attenuating the effects of long term EGF treatment on cell adhesion. Therefore, PG is essential for maintaining and regulating adhesive strength in keratinocytes largely through its contributions to desmosome assembly and structure. As a target for modulation by EGF, regulation of PG-dependent adhesion may play an important role during wound healing and tumor metastasis.
Yin
Taofei
T
Department of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Getsios
Spiro
S
Caldelari
Reto
R
Godsel
Lisa M
LM
Kowalczyk
Andrew P
AP
Müller
Eliane J
EJ
Green
Kathleen J
KJ
D000256:Adenoviridae / Q000378:metabolism; D022005:Adherens Junctions; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002478:Cells, Cultured; D003896:Desmosomes / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D017830:Octoxynol / Q000494:pharmacology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics* / Q000502:physiology
D003902:Detergents; D051176:beta Catenin; D051185:gamma Catenin; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D017830:Octoxynol; D066246:ErbB Receptors