Resistance of B16 melanoma cells to CD47-induced negative regulation of motility as a result of aberrant N-glycosylation of SHPS-1.
The adhesion receptor SHPS-1 activates the protein-tyrosine-phosphatase SHP-2 and thereby promotes integrin-mediated reorganization of the cytoskeleton. SHPS-1 also contributes to cell-cell communication through association with CD47. Although functional alteration of SHPS-1 is implicated in cellular transformation, the role of the CD47-SHPS-1 interaction in carcinogenesis has been unclear. A soluble SHPS-1 ligand (CD47-Fc) has now been shown to bind to Melan-a non-tumorigenic melanocytes but not to syngeneic B16F10 melanoma cells. Treatment of B16F10 cells with 1-deoxymannojirimycin, which prevents N-glycan processing, restored the ability of SHPS-1 derived from these cells to bind CD47-Fc in vitro, indicating that aberrant N-glycosylation of SHPS-1 impairs CD47 binding in B16F10 cells. CD47-Fc inhibited the migration of Melan-a cells but not that of B16F10 cells. However, a monoclonal antibody that reacts with SHPS-1 on both Melan-a and B16F10 cells inhibited the migration of both cell types similarly. CD47 binding induced proteasome-mediated degradation of SHPS-1 in a tyrosine phosphorylation-independent manner. Furthermore, overexpression of SHPS-1 reduced the level of tyrosine phosphorylation of focal adhesion kinase, and this effect was reversed by CD47 binding. These results suggest that CD47 binds to and thereby down-regulates SHPS-1 on adjacent cells, resulting in inhibition of cell motility. Resistance to this inhibitory mechanism may contribute to the highly metastatic potential of B16 melanoma.
Ogura
Takeshi
T
Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Noguchi
Tetsuya
T
Murai-Takebe
Reiko
R
Hosooka
Tetsuya
T
Honma
Nakayuki
N
Kasuga
Masato
M
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006031:Glycosylation; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008546:Melanoma, Experimental; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D012878:Skin Neoplasms; D012995:Solubility; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D039842:Neural Cell Adhesion Molecule L1; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex