Pleiotrophin, a multifunctional cytokine and growth factor, induces leukocyte responses through the integrin Mac-1.

Autor: Shen D; From the Schools of Molecular and., Podolnikova NP; Life Sciences, Arizona State University, Tempe, Arizona 85287 and., Yakubenko VP; Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614., Ardell CL; Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614., Balabiyev A; Life Sciences, Arizona State University, Tempe, Arizona 85287 and., Ugarova TP; Life Sciences, Arizona State University, Tempe, Arizona 85287 and Tatiana.Ugarova@asu.edu., Wang X; From the Schools of Molecular and xuwang@asu.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2017 Nov 17; Vol. 292 (46), pp. 18848-18861. Date of Electronic Publication: 2017 Sep 22.
DOI: 10.1074/jbc.M116.773713
Abstrakt: Pleiotrophin (PTN) is a multifunctional, cationic, glycosaminoglycan-binding cytokine and growth factor involved in numerous physiological and pathological processes, including tissue repair and inflammation-related diseases. PTN has been shown to promote leukocyte responses by inducing their migration and expression of inflammatory cytokines. However, the mechanisms through which PTN mediates these responses remain unclear. Here, we identified the integrin Mac-1 (αMβ2, CD11b/CD18) as the receptor mediating macrophage adhesion and migration to PTN. We also found that expression of Mac-1 on the surface of human embryonic kidney (HEK) 293 cells induced their adhesion and migration to PTN. Accordingly, PTN promoted Mac-1-dependent cell spreading and initiated intracellular signaling manifested in phosphorylation of Erk1/2. While binding to PTN, Mac-1 on Mac-1-expressing HEK293 cells appears to cooperate with cell-surface proteoglycans because both anti-Mac-1 function-blocking mAb and heparin were required to block adhesion. Moreover, biolayer interferometry and NMR indicated a direct interaction between the α M I domain, the major ligand-binding region of Mac-1, and PTN. Using peptide libraries, we found that in PTN the α M I domain bound sequences enriched in basic and hydrophobic residues, indicating that PTN conforms to the general principle of ligand-recognition specificity of the α M I domain toward cationic proteins/peptides. Finally, using recombinant PTN-derived fragments, we show that PTN contains two distinct Mac-1-binding sites in each of its constitutive domains. Collectively, these results identify PTN as a ligand for the integrin Mac-1 on the surface of leukocytes and suggest that this interaction may play a role in inflammatory responses.
(© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze: MEDLINE
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