Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Elizabeth Milward; Kee Jun Kim; Arek Szklarczyk; Thien Nguyen; Giorgia Melli; Mamatha Nayak; Deepa Deshpande; Chantel Fitzsimmons; Ahmet Hoke; Douglas Kerr; John W. Griffin; Peter A. Calabresi; Katherine Conant

doi:10.1016/j.jneuroim.2007.11.001

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Elizabeth Milward, Kee Jun Kim, Arek Szklarczyk, Thien Nguyen, Giorgia Melli, Mamatha Nayak, Deepa Deshpande, Chantel Fitzsimmons, Ahmet Hoke, Douglas Kerr, John W. Griffin, Peter A. Calabresi, Katherine Conant

School of Medicine

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	140-148
Number of pages	9
Journal	Journal of Neuroimmunology
Volume	193
Issue number	1-2
DOIs	https://doi.org/10.1016/j.jneuroim.2007.11.001
State	Published - Jan 2008

Keywords

MAG
MMP
Multiple sclerosis
Myelin
Proteinase

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Neurology
Clinical Neurology

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10.1016/j.jneuroim.2007.11.001

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title = "Cleavage of myelin associated glycoprotein by matrix metalloproteinases",

abstract = "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.",

keywords = "MAG, MMP, Multiple sclerosis, Myelin, Proteinase",

author = "Elizabeth Milward and Kim, {Kee Jun} and Arek Szklarczyk and Thien Nguyen and Giorgia Melli and Mamatha Nayak and Deepa Deshpande and Chantel Fitzsimmons and Ahmet Hoke and Douglas Kerr and Griffin, {John W.} and Calabresi, {Peter A.} and Katherine Conant",

note = "Funding Information: We would like to thank Hyoje Ryu for technical assistance. This work was supported in part by the National Institutes of Health (NS052580) and NMSS TR-3760-A-3.",

year = "2008",

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doi = "10.1016/j.jneuroim.2007.11.001",

language = "English (US)",

volume = "193",

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AU - Milward, Elizabeth

AU - Kim, Kee Jun

AU - Szklarczyk, Arek

AU - Nguyen, Thien

AU - Melli, Giorgia

AU - Nayak, Mamatha

AU - Deshpande, Deepa

AU - Fitzsimmons, Chantel

AU - Hoke, Ahmet

AU - Kerr, Douglas

AU - Griffin, John W.

AU - Calabresi, Peter A.

AU - Conant, Katherine

N1 - Funding Information: We would like to thank Hyoje Ryu for technical assistance. This work was supported in part by the National Institutes of Health (NS052580) and NMSS TR-3760-A-3.

PY - 2008/1

Y1 - 2008/1

N2 - 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.

AB - 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.

KW - MAG

KW - MMP

KW - Multiple sclerosis

KW - Myelin

KW - Proteinase

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Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Abstract

Keywords

ASJC Scopus subject areas

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