A role for the annexin A2 amino-terminal peptide in the plasmin-induced activation of human peripheral monocytes.
Plasmin is recognized as a potent signaling molecule in particular human monocytes, inducing a pro-inflammatory response. Recently, the annexin A2 heterotetramer, a plasmin receptor, was described at the surface of the human monocytes. Plasmin is initiating a signaling in monocytes by cleavage of the annexin A2 subunit of the receptor and the apparent dissociation of the heterotetramer at the surface of cell. However, the exact mechanism linking this dissociation and the activation of the intracellular pathway remains undefined. Here we report that the molecular mechanism of monocyte activation may rely on a new molecule containing the amino-terminal end of annexin A2 (A2NP) generated by plasmin cleavage of its receptor - the annexin A2 heterotetramer - as in vitro A2NP is able to mimic plasmin activation of the tyrosine kinase JAK1 and STAT3 and the subsequent increase in expression and release of monocyte/macrophage chemoattractant protein (MCP)-1, which is a major chemokine released by monocytes/macrophages. Additionally, we show that plasmin-induced the phosphorylation of STAT3 is similar to that of IL-6 and IL-31, and protease-activated receptor 1 does not affect plasmin-induced cytokine MCP-1 release in human monocytes. Finally, our data demonstrate that plasmin triggers the production of MCP-1 in macrophages in vivo. Thus, A2NP generated by plasmin cleavage of the annexin A2 heterotetramer could serve as a new proteolytically generated signaling molecule activating an associated transmembrane co-receptor, such as type I cytokine receptors.
Li
Qun
Q
State Key Laboratory of Medical Genomics at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Vascular Biology, 200025, Shanghai, China.
Ke
Fang
F
Zhang
Weiwei
W
Laumonnier
Yves
Y
Syrovets
Tatiana
T
Simmet
Thomas
T
Wang
Honglin
H
D000595:Amino Acid Sequence; D000818:Animals; D017306:Annexin A2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005341:Fibrinolysin / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D018000:Receptors, Peptide / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
C472822:ANXA2 protein, human; D017306:Annexin A2; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C502187:IL31 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D007378:Interleukins; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D018000:Receptors, Peptide; C065181:plasmin receptor; D005341:Fibrinolysin