Motegi Sei-Ichiro, Okazawa Hideki, Ohnishi Hiroshi, Sato Ryuji, Kaneko Yoriaki, Kobayashi Hisae, Tomizawa Kyoko, Ito Tomokazu, Honma Nakayuki, Bühring Hans-Jörg, Ishikawa Osamu, Matozaki Takashi
Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
EMBO J. 2003 Jun 2;22(11):2634-44. doi: 10.1093/emboj/cdg278.
SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47 and whose cytoplasmic region undergoes tyrosine phosphorylation and there by binds the protein tyrosine phosphatase SHP-2. Formation of this complex is implicated in regulation of cell migration by an unknown mechanism. A CD47-Fc fusion protein or antibodies to SHPS-1 inhibited migration of human melanoma cells or of CHO cells overexpressing SHPS-1. Overexpression of wild-type SHPS-1 promoted CHO cell migration, whereas expression of the SHPS-1-4F mutant, which lacks the phosphorylation sites required for SHP-2 binding, had no effect. Antibodies to SHPS-1 failed to inhibit migration of CHO cells expressing SHPS-1-4F. SHPS-1 ligands induced the dephosphorylation of SHPS-1 and dissociation of SHP-2. Antibodies to SHPS-1 also enhanced Rho activity and induced both formation of stress fibers and adoption of a less polarized morphology in melanoma cells. Our results suggest that engagement of SHPS-1 by CD47 prevents the positive regulation of cell migration by this protein. The CD47- SHPS-1 system and SHP-2 might thus contribute to the inhibition of cell migration by cell-cell contact.
信号调节蛋白-1（SHPS-1）是一种跨膜蛋白，其细胞外区域与CD47相互作用，其细胞质区域发生酪氨酸磷酸化，进而结合蛋白酪氨酸磷酸酶SHP-2。这种复合物的形成通过未知机制参与细胞迁移的调节。CD47-Fc融合蛋白或抗SHPS-1抗体可抑制人黑色素瘤细胞或过表达SHPS-1的CHO细胞的迁移。野生型SHPS-1的过表达促进CHO细胞迁移，而缺乏SHP-2结合所需磷酸化位点的SHPS-1-4F突变体的表达则没有影响。抗SHPS-1抗体未能抑制表达SHPS-1-4F的CHO细胞的迁移。SHPS-1配体诱导SHPS-1去磷酸化和SHP-2解离。抗SHPS-1抗体还增强了Rho活性，并诱导黑色素瘤细胞中应力纤维的形成和采用较少极化的形态。我们的结果表明，CD47与SHPS-1的结合阻止了该蛋白对细胞迁移的正向调节。因此，CD47-SHPS-1系统和SHP-2可能通过细胞间接触参与细胞迁移的抑制。
