Cleavage of myelin associated glycoprotein by matrix metalloproteinases.
Derivative myelin associated glycoprotein (dMAG) results from proteolysis of transmembrane MAG and can inhibit axonal growth. We have tested the ability of certain matrix metalloproteinases (MMPs) elevated with inflammatory and demyelinating diseases to cleave MAG. We show MMP-2, MMP-7 and MMP-9, but not MMP-1, cleave recombinant human MAG. Cleavage by MMP-7 occurs at Leu 509, just distal to the transmembrane domain and, to a lesser extent, at Met 234. We also show that MMP-7 cleaves MAG expressed on the external surface of CHO cells, releasing fragments that accumulate in the medium over periods of up to 48 h or more and that are able to inhibit outgrowth by dorsal root ganglion (DRG) neurons. We conclude that MMPs may have the potential both to disrupt MAG dependent axon-glia communication and to generate bioactive fragments that can inhibit neurite growth.
Milward
Elizabeth
E
School of Biomedical Sciences, The University of Newcastle and the Hunter Medical Research Institute, Callaghan, New South Wales 2308, Australia.
Kim
Kee Jun
KJ
Szklarczyk
Arek
A
Nguyen
Thien
T
Melli
Giorgia
G
Nayak
Mamatha
M
Deshpande
Deepa
D
Fitzsimmons
Chantel
C
Hoke
Ahmet
A
Kerr
Douglas
D
Griffin
John W
JW
Calabresi
Peter A
PA
Conant
Katherine
K
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005727:Ganglia, Spinal / Q000254:growth & development; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000201:enzymology; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D018992:Myelin-Associated Glycoprotein; D010446:Peptide Fragments; D011994:Recombinant Proteins; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7