Chromogranin A binds to alpha v beta 6-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 alpha v beta 6-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 alpha v beta 3, alpha v beta 5, alpha v beta 8, alpha 5 beta 1, alpha 1 beta 1, alpha 3 beta 1, alpha 6 beta 4, alpha 6 beta 7 and alpha 9 beta 1. Structure-activity studies showed that the entire CgA(39-63) region is crucial for alpha v beta 6 recognition (K (i) = 7 nM). 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 alpha v beta 6 regulates keratinocyte physiology in wound healing.