title: ADAM9 disintegrin domain activates human neutrophils through an autocrine circuit involving integrins and CXCR2.
abstract: ADAM9 is a member of the ADAM family whose expression positively correlates with tumor progression. Besides the metalloprotease activity, ADAM9D interacts with different integrins, modulating cell-adhesion events. Previous studies pointed to an important role for neutrophils in tumor development, as the inhibition of neutrophil migration or depletion of this immune cell impairs tumor growth. However, our understanding of the molecular mechanisms involved in this process, as well as the main key players acting on neutrophils, is very limited. Here, we investigated the possible modulatory effects of ADAM9D on human neutrophil functions. Our results show that ADAM9D promotes neutrophil activation and chemotaxis in a process that depends on the engagement ofαvβ3andα9β1integrins and on the activation of PI3K/Akt and MAPK signaling pathway. ADAM9D impairs migration of neutrophils toward fMLP, LTB4, and IL-8 as classic chemoattractants. This effect is blocked by PTX, a G(i)PCR inhibitor. Furthermore, CXCR2 antagonists RPTX and SB225002 also impaired neutrophil chemotaxis in response to ADAM9D, suggesting a hierarchical cross-talk of integrins with CXCR2. Our results indicate that ADAM9D activates neutrophil functions and may be implicated in the inflammatory events associated with cancer and other disorders.
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Amendola
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil.
authors.forename: Ana Carolina B M
authors.initials: AC
authors.lastname: Martin
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil.
authors.forename: Heloísa S
authors.initials: HS
authors.lastname: Selistre-de-Araújo
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil.
authors.forename: Heitor A
authors.initials: HA
authors.lastname: Paula-Neto
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Saldanha-Gama
authors.affiliation: *Laboratório de Farmacologia Celular e Molecular, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and Laboratório de Bioquímica e Biologia Molecular, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, Brazil barja-fidalgo@uerj.br.
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
keywords: IL-8; apoptosis; chemotaxis; granulocyte; signal transduction