Journal article
L1 Is Sequentially Processed by Two Differently Activated Metalloproteases and Presenilin/γ-Secretase and Regulates Neural Cell Adhesion, Cell Migration, and Neurite Outgrowth
Molecular and cellular biology, Vol.25(20), pp.9040-9053
10/2005
DOI: 10.1128/MCB.25.20.9040-9053.2005
PMCID: PMC1265787
PMID: 16199880
Abstract
The immunoglobulin superfamily recognition molecule L1 plays important functional roles in the developing and adult nervous system. Metalloprotease-mediated cleavage of this adhesion molecule has been shown to stimulate cellular migration and neurite outgrowth. We demonstrate here that L1 cleavage is mediated by two distinct members of the disintegrin and metalloprotease family, ADAM10 and ADAM17. This cleavage is differently regulated and leads to the generation of a membrane bound C-terminal fragment, which is further processed through γ-secretase activity. Pharmacological approaches with two hydroxamate-based inhibitors with different preferences in blocking ADAM10 and ADAM17, as well as loss of function and gain of function studies in murine embryonic fibroblasts, showed that constitutive shedding of L1 is mediated by ADAM10 while phorbol ester stimulation or cholesterol depletion led to ADAM17-mediated L1 cleavage. In contrast,
N
-methyl-
d
-aspartate treatment of primary neurons stimulated ADAM10-mediated L1 shedding. Both proteases were able to affect L1-mediated adhesion and haptotactic migration of neuronal cells. In particular, both proteases were involved in L1-dependent neurite outgrowth of cerebellar neurons. Thus, our data identify ADAM10 and ADAM17 as differentially regulated L1 membrane sheddases, both critically affecting the physiological functions of this adhesion protein.
Details
- Title: Subtitle
- L1 Is Sequentially Processed by Two Differently Activated Metalloproteases and Presenilin/γ-Secretase and Regulates Neural Cell Adhesion, Cell Migration, and Neurite Outgrowth
- Creators
- Thorsten Maretzky - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyMarc Schulte - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyAndreas Ludwig - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyStefan Rose-John - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyCarl Blobel - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyDieter Hartmann - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyPeter Altevogt - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyPaul Saftig - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, GermanyKarina Reiss - Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, Germany
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.25(20), pp.9040-9053
- DOI
- 10.1128/MCB.25.20.9040-9053.2005
- PMID
- 16199880
- PMCID
- PMC1265787
- NLM abbreviation
- Mol Cell Biol
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Publisher
- American Society for Microbiology
- Language
- English
- Date published
- 10/2005
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094519702771
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