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First published online 12 August 2003
doi: 10.1242/jcs.00699
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Research Article |
1 Institute of Molecular Pathology, University of Copenhagen, Frederik's
vej 11, 2100 Copenhagen, Denmark
2 Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
3 Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, D-89081
Ulm, Germany
4 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA 02215, USA
Author for correspondence (e-mail:
ullaw{at}pai.ku.dk)
Accepted 5 June 2003
Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We showed that the highest levels of ADAM12 mRNA were detected in preadipocytes at the critical stage when preadipocytes become permissive for adipogenic differentiation. Furthermore, as assessed by immunostaining, ADAM12 was transiently expressed at the cell surface concomitant with the reduced activity of ß1 integrin. Co-immunoprecipitation studies indicated the formation of ADAM12/ß1 integrin complexes in these preadipocytes. Overexpression of ADAM12 at the cell surface of 3T3-L1 preadipocytes achieved by transient transfection or retroviral transduction led to the disappearance of the extensive network of actin stress fibers that are characteristic of these cells, and its reorganization into a cortical network located beneath the cell membrane. The cells became more rounded, exhibited fewer vinculin-positive focal adhesions, and adhered less efficiently to fibronectin in attachment assays. Moreover, ADAM12-expressing cells were more prone to apoptosis, which could be prevented by treating the cells with ß1-activating antibodies. A reduced and re-organized fibronectin-rich extracellular matrix accompanied these changes. In addition, ß1 integrin was more readily extracted with Triton X-100 from cells overexpressing ADAM12 than from control cells. Collectively, these results show that surface expression of ADAM12 impairs the function of ß1 integrins and, consequently, alters the organization of the actin cytoskeleton and extracellular matrix. These events may be necessary for early adipocyte differentiation.
Key words: ADAM12, ß1 integrin, Actin cytoskeleton, Extracellular matrix, Adipogenesis
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