Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 15, Pages 5420-5425Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0501676102
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- NIAMS NIH HHS [R01 AR 41836, R01 AR 048266, R01 AR 43380, R01 AR041836, R01 AR043380, R01 AR048266] Funding Source: Medline
- NIDCR NIH HHS [P01 DE012328, P01 DE 12328] Funding Source: Medline
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Plakoglobin (PG) is a member of the Armadillo family of adhesion/signaling proteins and has been shown to play a critical role in the organization of desmosomes and tissue integrity. Because dissolution of intercellular junctions is frequently an initial step in the onset of epithelial cell migration, we examined whether loss of PG promotes cell motility by compromising adhesive strength. Keratinocyte cultures established from PG-/- mice exhibited weakened adhesion and increased motility in transwell migration assays; both were restored by reintroducing PG through adenoviral infection. interestingly, single PG-/- cells also exhibited increased motility, which was suppressed by reintroducing PG, but not the closely related beta-catenin. Whereas both N- and C-terminally truncated PG deletion mutants restored adhesion, only N-terminally deleted PG, but not C-terminally deleted PG, suppressed single-cell migration. Furthermore, both the chemical inhibitor PP2 and dominant-negative Src tyrosine kinase inhibited single-cell motility in PG-/- cells, whereas constitutively active Src overcame the inhibitory effect of PG. These data demonstrate that PG strengthens adhesion and suppresses motility in mouse keratinocytes, through both intercellular adhesion-dependent and -independent mechanisms, the latter of which may involve suppression of Src signaling through a mechanism requiring the PG C terminus.
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