Src-mediated caveolin-1 phosphorylation regulates intestinal epithelial restitution by altering Ca(2+) influx after wounding

Early mucosal restitution occurs as a consequence of intestinal epithelial cell (IEC) migration to reseal superficial wounds, but its exact mechanism remains largely unknown. Caveolin-1 (Cav1), a major component associated with caveolar lipid rafts in the plasma membrane, is implicated in many aspec...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2014-04, Vol.306 (8), p.G650-G658
Main Authors: Rathor, Navneeta, Zhuang, Ran, Wang, Jian-Ying, Donahue, James M, Turner, Douglas J, Rao, Jaladanki N
Format: Article
Language:English
Subjects:
Calcium - metabolism
Caveolin 1 - metabolism
Cell Movement - physiology
Cells, Cultured
Humans
Intestinal Mucosa - injuries
Intestinal Mucosa - metabolism
Signal Transduction
src-Family Kinases - metabolism
Wound Healing - physiology
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Summary:Early mucosal restitution occurs as a consequence of intestinal epithelial cell (IEC) migration to reseal superficial wounds, but its exact mechanism remains largely unknown. Caveolin-1 (Cav1), a major component associated with caveolar lipid rafts in the plasma membrane, is implicated in many aspects of cellular functions. This study determined if c-Src kinase (Src)-induced Cav1 phosphorylation promotes intestinal epithelial restitution after wounding by activating Cav1-mediated Ca(2+) signaling. Src directly interacted with Cav1, formed Cav1-Src complexes, and phosphorylated Cav1 in IECs. Inhibition of Src activity by its chemical inhibitor PP2 or suppression of the functional caveolin scaffolding domain by caveolin-scaffolding domain peptides prevented Cav1-Src interaction, reduced Cav1 phosphorylation, decreased Ca(2+) influx, and inhibited cell migration after wounding. Disruption of caveolar lipid raft microdomains by methyl-β-cyclodextrin reduced Cav1-mediated Ca(2+) influx and repressed epithelial restitution. Moreover, Src silencing prevented subcellular redistribution of phosphorylated Cav1 in migrating IECs. These results indicate that Src-induced Cav1 phosphorylation stimulates epithelial restitution by increasing Cav1-mediated Ca(2+) signaling after wounding, thus contributing to the maintenance of gut mucosal integrity under various pathological conditions.
ISSN:1522-1547
DOI:10.1152/ajpgi.00003.2014