Neutrophil apoptosis: selective regulation by different ligands of integrin alphaMbeta2.
Neutrophils undergo spontaneous apoptosis, but their survival can be extended during inflammatory responses. alpha(M)beta(2) is reported either to delay or accelerate neutrophil apoptosis, but the mechanisms by which this integrin can support such diametrically opposed responses are poorly understood. The abilities of closely related alpha(M)beta(2) ligands, plasminogen and angiostatin, derived from plasminogen, as well as fibrinogen and its two derivative alpha(M)beta(2) recognition peptides, P1 and P2-C, differed markedly in their effects on neutrophil apoptosis. Plasminogen, fibrinogen, and P2-C suppressed apoptosis via activation of Akt and ERK1/2 kinases, while angiostatin and P1 failed to activate these prosurvival pathways and did not prevent neutrophil apoptosis. Using cells transfected with alpha(M)beta(2) or its individual alpha(M) or beta(2) subunits, and purified receptors and its constituent chains, we show that engagement of both subunits with prosurvival ligands is essential for induction of the prosurvival response. Hence, engagement of a single integrin by closely related ligands can induce distinct signaling pathways, which can elicit distinct cellular responses.
Pluskota
Elzbieta
E
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Soloviev
Dmitry A
DA
Szpak
Dorota
D
Weber
Christian
C
Plow
Edward F
EF
D043168:Angiostatins / Q000502:physiology; D017209:Apoptosis; D002478:Cells, Cultured; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology*; D010958:Plasminogen / Q000502:physiology; D021122:Protein Subunits
D008024:Ligands; D016177:Macrophage-1 Antigen; D021122:Protein Subunits; D043168:Angiostatins; D005340:Fibrinogen; D010958:Plasminogen