Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates alpha2beta1 integrin-mediated cell adhesion, migration and proliferation.
The alpha2beta1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, competitively interacts with the alpha2beta1 integrin, thereby inhibiting collagen binding. When immobilized in plate wells, ALT-C supports the adhesion of fibroblasts as well as of human vein endothelial cells (HUVEC) and does not detach cells previously bound to collagen I. ALT-C is a strong inducer of HUVEC proliferation in vitro. Gene expression analysis was done using an Affimetrix HU-95A probe array with probe sets of approximately 10,000 human genes. In human fibroblasts growing on collagen-coated plates, ALT-C up-regulates the expression of several growth factors including vascular endothelial growth factor, as well as some cell cycle control genes. Up-regulation of the vascular endothelial growth factor gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates protein kinase B phosphorylation, a signaling event involved in endothelial cell survival and angiogenesis. In human neutrophils, ALT-C has a potent chemotactic effect modulated by the intracellular signaling cascade characteristic of integrin-activated pathways. Thus, ALT-C acts as a survival factor, promoting adhesion, migration and endothelial cell proliferation after binding to alpha2beta1 integrin on the cell surface. The biological activities of ALT-C may be helpful as a therapeutic strategy in tissue regeneration as well as in the design of new therapeutic agents targeting alpha2beta1 integrin.
Selistre-de-Araujo
H S
HS
Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP, Brazil. hsaraujo@power.ufscar.br
Cominetti
M R
MR
Terruggi
C H B
CH
Mariano-Oliveira
A
A
De Freitas
M S
MS
Crepin
M
M
Figueiredo
C C
CC
Morandi
V
V
D000818:Animals; D017837:Bothrops; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003435:Crotalid Venoms / Q000737:chemistry*; D019483:Disintegrins / Q000302:isolation & purification / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D038982:Integrin alpha2beta1 / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*
D003435:Crotalid Venoms; D019483:Disintegrins; D038982:Integrin alpha2beta1; D010975:Platelet Aggregation Inhibitors; C481346:alternagin-C