title: Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice.
abstract: 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 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 CgA(39-63) region is crucial for αvβ6 recognition (K(i) = 7 nM). This region contains an RGD site (residues CgA(43-45)) followed by an amphipathic α-helix (residues CgA(47-63)), 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.
authors.affiliation: Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gasparri
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Barbara
authors.initials: B
authors.lastname: Colombo
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001667:Binding, Competitive; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D053379:Chromogranin A / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D012633:Secretin / Q000031:analogs & derivatives / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; D053379:Chromogranin A; D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; C073878:integrin alphavbeta6; D012633:Secretin; C032333:vasectrin I; C047981:arginyl-glycyl-aspartic acid