SHPS-1 regulates integrin-mediated cytoskeletal reorganization and cell motility

Abstract

The transmembrane glycoprotein SHPS‐1 binds the protein tyrosine phosphatase SHP‐2 and serves as its substrate. Although SHPS‐1 has been implicated in growth factor‐ and cell adhesion‐induced signaling, its biological role has remained unknown. Fibroblasts homozygous for expression of an SHPS‐1 mutant lacking most of the cytoplasmic region of this protein exhibited increased formation of actin stress fibers and focal adhesions. They spread more quickly on fibronectin than did wild‐type cells, but they were defective in subsequent polarized extension and migration. The extent of adhesion‐induced activation of Rho, but not that of Rac, was also markedly reduced in the mutant cells. Activation of the Ras–extracellular signal‐regulated kinase signaling pathway and of c‐Jun N‐terminal kinases by growth factors was either unaffected or enhanced in the mutant fibroblasts. These results demonstrate that SHPS‐1 plays crucial roles in integrin‐mediated cytoskeletal reorganization, cell motility and the regulation of Rho, and that it also negatively modulates growth factor‐induced activation of mitogen‐activated protein kinases.

Src homology 2 domain‐containing protein tyrosine phosphatase substrate 1 regulates the induction of Langerhans cell maturation

“…The generation of mutant mice that lack most of the cytoplasmic region of SHPS-1 has been previously described [48]. Mice were bred and maintained in the Institute of Experimental Animal Research of Gunma University or Kobe University Graduate School of Medicine under specific pathogen-free conditions.…”

“…The mice were backcrossed onto the C57BL/6 background over five generations. Genotyping of the mice was performed by PCR analysis as previously reported [48]. Female C57BL/6 mice (6-to 8-week-old) were purchased from Charles River Japan (Tokyo, Japan).…”

Resistance of B16 Melanoma Cells to CD47-induced Negative Regulation of Motility as a Result of Aberrant N-Glycosylation of SHPS-1

“…Given the role of SHPS-1 in cytoskeletal reorganization (20,21) and the fact that B16F10 cells are highly motile whereas Melan-a cells are not (30), we focused our attention on the effect of CD47 binding to SHPS-1 on cell migration. Quantitative analysis with a Boyden chamber assay revealed that the number of Melan-a cells that migrated through a membrane coated with fibronectin was reduced by ϳ20% in the presence of CD47-Fc (Fig.…”

“…Binding of CD47 to Cells Down-regulates SHPS-1 Expression-SHPS-1 promotes cell migration by recruiting SHP-2 to the cell membrane and thereby activating its phosphatase activity (20), suggesting that CD47 binding to cells might inhibit cell motility by abrogating this function of SHPS-1. We observed that the expression level of SHPS-1 in Melan-a cells incubated with CD47-Fc for 6 h was substantially lower than that apparent in cells incubated with the control Fc fragment for a similar period (Fig.…”

“…SHPS-1 negatively or positively regulates intracellular signaling initiated either by tyrosine kinase-coupled receptors for growth factors or by cell adhesion to extracellular matrix proteins (18,19). With the use of mice lacking most of the cytoplasmic region of SHPS-1 (20,21), we recently showed that this protein plays an important role both in integrin-mediated cytoskeletal reorganization and in cell migration. In addition, studies with dominant negative or loss-of-function mutant proteins have established SHP-2 as a signaling component essential for cell adhesion and migration as well as cytoskeletal organization (22)(23)(24)(25)(26).…”