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JCS ePress
online publication date 12 Aug 2003
doi: 10.1242/jcs.00699
Research Article
ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating 
1 integrin function
Nobuko Kawaguchi,
Christina Sundberg,
Marie Kveiborg,
Behzad Moghadaszadeh,
Meena Asmar,
Nikolaj Dietrich,
Charles K. Thodeti,
Finn C. Nielsen,
Peter Möller,
Arthur M. Mercurio,
Reidar Albrechtsen,
and
Ulla M. Wewer*
* Author for correspondence (e-mail: ullaw{at}pai.ku.dk)
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 
1 integrin. Co-immunoprecipitation studies indicated the formation of ADAM12/1 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 1-activating antibodies. A reduced and re-organized fibronectin-rich extracellular matrix accompanied these changes. In addition, 1 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 1 integrins and, consequently, alters the organization of the actin cytoskeleton and extracellular matrix. These events may be necessary for early adipocyte differentiation.
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