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Molecular and Cellular Biology, October 2005, p. 9040-9053, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.9040-9053.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

L1 Is Sequentially Processed by Two Differently Activated Metalloproteases and Presenilin/{gamma}-Secretase and Regulates Neural Cell Adhesion, Cell Migration, and Neurite Outgrowth

Thorsten Maretzky,1 Marc Schulte,1 Andreas Ludwig,1 Stefan Rose-John,1 Carl Blobel,2 Dieter Hartmann,3 Peter Altevogt,4,{dagger} Paul Saftig,1,{dagger}* and Karina Reiss1,{dagger}

Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, Germany,1 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021,2 Department for Human Genetics, K. U. Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium,3 German Cancer Research Center, D-69120 Heidelberg, Germany4

Received 10 June 2005/ Accepted 14 June 2005

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 {gamma}-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.

* Corresponding author. Mailing address: Biochemical Institute, Christian Albrechts University Kiel, D-24098 Kiel, Germany. Phone: 49/431-8802216. Fax: 49/431-8802238. E-mail: psaftig{at}biochem.uni-kiel.de.

{dagger} Contributed equally to this work.

Molecular and Cellular Biology, October 2005, p. 9040-9053, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.9040-9053.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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