Metalloproteinase-mediated release of the ectodomain of L1 adhesion molecule.
The L1 adhesion molecule is an approx. 200-220 kDa type I membrane glycoprotein belonging to the immunoglobulin (Ig) superfamily. L1 can bind in a homotypic fashion and was shown to support integrin-mediated binding via RGDs in the 6th Ig-like domain. In addition to its cell-surface expression, L1 can occur in the extracellular matrix (ECM). Here we demonstrate that L1 is constitutively released from the cell surface by membrane-proximal cleavage. L1 shed from B16F10 melanoma cells remains intact and can serve as substrate for integrin-mediated cell adhesion and migration. The release of L1 occurs in mouse and human cells and is blocked by the metalloproteinase inhibitor TAPI (Immunex compound 3). This compound has been shown previously to block release of L-selectin and TNF-alpha which is mediated by the membrane-bound metalloproteinase TNF-alpha converting enzyme (TACE). Using CHO cells that are low in TACE expression and do not release L-selectin we demonstrate that L1 release is distinct from L-selectin shedding. We propose that cell-surface release may be necessary for the conversion of L1 from a membrane into an ECM protein.
Tumor Immunology Programme, German Cancer Research Center, D-69120 Heidelberg, Germany.
S
S
Beer
M
M
Oleszewski
P
P
Gutwein
C
C
Geiger
P
P
Altevogt
D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D006825:Hybridomas; D006877:Hydroxamic Acids / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex; D008545:Melanoma; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D009101:Multiple Myeloma; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D009447:Neuroblastoma; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000378:metabolism
D000954:Antigens, Surface; D004151:Dipeptides; D006877:Hydroxamic Acids; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D019006:Neural Cell Adhesion Molecules; D011480:Protease Inhibitors; D019041:L-Selectin; D008666:Metalloendopeptidases