Chromogranin A binds to alphavbeta6-integrin and promotes wound healing in mice.

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 Asp(45)Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp(45)Glu mutants, could selectively recognize the alphavbeta6-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 alphavbeta3, alphavbeta5, alphavbeta8, alpha5beta1, alpha1beta1, alpha3beta1, alpha6beta4, alpha6beta7 and alpha9beta1. Structure-activity studies showed that the entire CgA(39-63) region is crucial for alphavbeta6 recognition (K (i)=7nM). This region contains an RGD site (residues CgA(43-45)) followed by an amphipathic alpha-helix (residues CgA(47-63)), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/alpha-helix motif of CgA with alphavbeta6 regulates keratinocyte physiology in wound healing.