Cleavage of chromogranin A N-terminal domain by plasmin provides a new mechanism for regulating cell adhesion.
It has been proposed that chromogranin A (CgA), a protein secreted by many normal and neoplastic neuroendocrine cells, can play a role as a positive or a negative modulator of cell adhesion. The mechanisms that regulate these extracellular functions of CgA are unknown. We show here that plasmin can regulate the anti/pro-adhesive activity of CgA by proteolytic cleavage of the N-terminal domain. Limited proteolytic processing decreased its anti-adhesive activity and induced pro-adhesive effects in fibronectin or serum-dependent fibroblast adhesion assays. Cleavage of Lys(77)-Lys(78) dibasic site in CgA(1-115) was relatively rapid and associated with an increase of pro-adhesive effect. In contrast, antibodies against the region 53-90 enhanced the anti-adhesive activity of CgA and CgA(1-115). Structure-activity relationship studies showed that the conserved region 47-64 (RILSILRHQNLLKELQDL) is critical for both pro- and anti-adhesive activity. These findings suggest that CgA might work on one hand as a negative modulator of cell adhesion and on the other hand as a precursor of positive modulators, the latter requiring proteolytic processing for activation. Given the importance of plasminogen activation in tissue invasion and remodeling, the interplay between CgA and plasmin could provide a novel mechanism for regulating fibroblast adhesion and function in neuroendocrine tumors.
Colombo
Barbara
B
Department of Biological and Technological Research, San Raffaele H. Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
Longhi
Renato
R
Marinzi
Chiara
C
Magni
Fulvio
F
Cattaneo
Angela
A
Yoo
Seung Hyun
SH
Curnis
Flavio
F
Corti
Angelo
A
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002448:Cell Adhesion / Q000502:physiology*; D053379:Chromogranin A; D002864:Chromogranins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005341:Fibrinolysin / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data
D000911:Antibodies, Monoclonal; D053379:Chromogranin A; D002864:Chromogranins; C506155:chromogranin A, mouse; D005341:Fibrinolysin