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.
School of Biomedical Sciences, The University of Newcastle and the Hunter Medical Research Institute, Callaghan, New South Wales 2308, Australia.
Elizabeth
E
Milward
Kee Jun
KJ
Kim
Arek
A
Szklarczyk
Thien
T
Nguyen
Giorgia
G
Melli
Mamatha
M
Nayak
Deepa
D
Deshpande
Chantel
C
Fitzsimmons
Ahmet
A
Hoke
Douglas
D
Kerr
John W
JW
Griffin
Peter A
PA
Calabresi
Katherine
K
Conant
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