Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice
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Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp45Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp45Glu mutants, could selectively recognize the αvβ6-integrin on keratinocytes (a cell-adhesion receptor that is up-regulated during wound healing) and regulate keratinocyte adhesion, proliferation, and migration. No binding was observed to other integrins such as αvβ3, αvβ5, αvβ8, α5β1, α1β1, α3β1, α6β4, α6β7 and α9β1. Structure–activity studies showed that the entire CgA39–63 region is crucial for αvβ6 recognition (K i = 7 nM). This region contains an RGD site (residues CgA43–45) followed by an amphipathic α-helix (residues CgA47–63), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/α-helix motif of CgA with αvβ6 regulates keratinocyte physiology in wound healing.
KeywordsChromogranin-A Vasostatin-1 αv/β6 Integrin Wound healing
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 9965 and 9180), and Alleanza Contro il Cancro (ACC) of Italy.
Conflict of interest
The authors declare no conflicts of interest.
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