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PMID:14761956

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Citation

Naus, S, Richter, M, Wildeboer, D, Moss, M, Schachner, M and Bartsch, JW (2004) Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J. Biol. Chem. 279:16083-90

Abstract

The neural cell adhesion molecule "close homologue of L1," termed CHL1, has functional importance in the nervous system. CHL1 is expressed as a transmembrane protein of 185 kDa, and ectodomain shedding releases soluble fragments relevant for its physiological function. Here we describe that ADAM8, a member of the family of metalloprotease disintegrins cleaves a CHL1-Fc fusion protein in vitro at two sites corresponding to release of the extracellular domain of CHL1 in fibronectin (FN) domains II (125 kDa) and V (165 kDa), inhibited by batimastat (BB-94). Cleavage of CHL1-Fc in the 125-kDa fragment was not detectable under non-reducing conditions arguing that cleavage resulting in the 165-kDa fragment is more relevant in releasing soluble CHL1 in vivo. In cells transfected with full-length ADAM8, membrane proximal cleavage of CHL1 was similar and not stimulated by phorbol ester 12-O-tetradecanoylphorbol-13-acetate and pervanadate. No cleavage of CHL1 was observed in cells expressing either inactive ADAM8 with a Glu330 to Gln exchange (EQ-A8), or active ADAM10 and ADAM17. Consequently, processing of CHL1 was hardly detectable in brain extracts of ADAM8-deficient mice but enhanced in a neurodegenerative mouse mutant. CHL1 processed by ADAM8 in supernatants of COS-7 cells and in co-culture with cerebellar granule neurons was very potent in stimulating neurite outgrowth and suppressing neuronal cell death, not observed in cells co-transfected with CHL1/EQ-A8, CHL1/ADAM10, or CHL1/ADAM17. Taken together, we propose that ADAM8 plays an important role in physiological and pathological cell interactions by a specific release of functional CHL1 from the cell surface.

Links

PubMed Online version:10.1074/jbc.M400560200

Keywords

ADAM Proteins; Animals; Antigens, CD/physiology; Cell Communication/physiology; Cell Death/physiology; Membrane Proteins/physiology; Metalloendopeptidases/physiology; Mice; Mutation; Neurites/physiology; Neurites/ultrastructure; Neurons/cytology; Neurons/physiology; Peptide Fragments; Protein Structure, Tertiary

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NCHL1

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q05910

F

Seeded From UniProt

complete

MOUSE:NCHL1

involved_in

GO:0043524: negative regulation of neuron apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADAM8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70232

F

Seeded From UniProt

complete

MOUSE:ADAM8

enables

GO:0008237: metallopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ADAM8

involved_in

GO:0051044: positive regulation of membrane protein ectodomain proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADAM8

involved_in

GO:0043524: negative regulation of neuron apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADA17

enables

GO:0008237: metallopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ADA10

enables

GO:0008237: metallopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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