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¹ Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
² Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA
³ Burnham Institute for Medical Research, La Jolla, California 92037, USA
⁴ Program of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan

SHPS-1/SIRP1 is a transmembrane glycoprotein that belongs to the immunoglobulin (Ig) super family. In the present study, we show that SHPS-1 strongly associates with Concanavalin A (Con A), a plant lectin obtained from jack beans. Further studies with SHPS-1 mutants reveal that the extracellular domain of SHPS-1 containing the Ig sequence is responsible for its association with Con A. Con A treatment induces cross-linking and multimerization of the SHPS-1 protein in the plasma membrane, accompanied by its tyrosine phosphorylation and recruitment of SHP-2. In contrast, Ricinus communis agglutinin (RCA), another lectin obtained from castor bean, does not bind or activate tyrosine phosphorylation of SHPS-1. Moreover, Con A activates Akt in a SHP-2-dependent manner. Treatment of mouse embryonic fibroblasts (MEFs) with Con A induces secretion of matrix metalloproteinase (MMP)-9, a phenomenon that is inhibited in cells expressing YF mutant of SHPS-1, a dominant negative form of Akt or in cells pre-treated with an Akt inhibitor, LY294002 or extracellular-signal regulated kinase (Erk) inhibitor, U0126. In addition, expression of the YF mutant of SHPS-1 inhibits Con A-dependent activation of Akt and Erk kinases. Taken together, our results suggest that SHPS-1 is a receptor for Con A that mediates Con A-dependent MMP-9 secretion through SHP-2-promoted activation of both Akt and Erk pathways.

^* Correspondence: E-mail: mhamagu{at}med.nagoya-u.ac.jp