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Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice

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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 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.

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Abbreviations

CgA:

Chromogranin-A

hCgA:

Human CgA

rCgA:

Recombinant CgA

VS-1:

Vasostatin-1

STV:

Streptavidin

HRP:

Peroxidase

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Acknowledgments

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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Authors and Affiliations

  1. Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132, Milan, Italy

    Flavio Curnis, Anna Maria Gasparri, Barbara Colombo & Angelo Corti

  2. Istituto di Chimica del Riconoscimento Molecolare, CNR, 20131, Milan, Italy

    Renato Longhi

  3. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132, Milan, Italy

    Silvia D’Alessio

  4. Laboratory of Oncology, Experimental Therapy Unit, G. Gaslini Children’s Hospital, 16148, Genoa, Italy

    Fabio Pastorino & Mirco Ponzoni

Authors
  1. Flavio Curnis
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  2. Anna Maria Gasparri
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  3. Renato Longhi
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  4. Barbara Colombo
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  5. Silvia D’Alessio
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  6. Fabio Pastorino
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  7. Mirco Ponzoni
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  8. Angelo Corti
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Corresponding author

Correspondence to Angelo Corti.

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Curnis, F., Gasparri, A.M., Longhi, R. et al. Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice. Cell. Mol. Life Sci. 69, 2791–2803 (2012). https://doi.org/10.1007/s00018-012-0955-z

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  • DOI: https://doi.org/10.1007/s00018-012-0955-z

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