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RESEARCH ARTICLE |
Vß3
Ecole Normale Supérieure de Lyon, 46
allée d'Italie, 69364 Lyon Cedex 07,
France
*
Present address: Institut Albert-Bonniot, LEDAC (UMR5538),
Faculté de Medecine, F 38706 La Tronche Cedex,
France
Author for correspondence (e-mail:
martin.pfaff{at}ujf-grenoble.fr
)
Accepted May 1, 2001
Macrophages and osteoclasts develop unique contact sites with the
extracellular matrix called podosomes. Podosomes have been associated with
migratory and invasive cell characteristics, but a basic mechanism outlining
their function is lacking. We have used chicken and human monocytes
differentiating in vitro into osteoclast-like cells in the presence of
RANKL-ODF to study these cytoskeletal structures. During the differentiation
process, podosomes are redistributed from the cell body in early macrophages
to the cell periphery in increasingly spread and multinucleated cells
expressing high levels of integrin 
Vß3. Immunofluorescence with
anti-phosphotyrosine antibodies revealed increased tyrosine-phosphorylation at
the basal tips of these podosomes. RANKL-ODF treatment reinforced the
peripheral location of podosomes and initiated their partial fusion to larger
F-actin-containing structures that displayed reduced levels of tyrosine
phosphorylation. Paxillin and the FAK-related kinase Pyk2 colocalized with
integrin Vß3 in the juxtamembrane region surrounding individual
podosomes. In lysates of macrophages and differentiated osteoclasts both
paxillin and Pyk2 associated with synthetic and recombinant polypeptides
containing the C-terminal region of the integrin ß3 cytoplasmic domain.
These in vitro interactions were direct and they were abolished by
substitutions in the ß3 integrin peptides known to disrupt integrin
function in vivo. The marked adhesion-dependent tyrosine-phosphorylation of
Pyk2 and paxillin however did not detectably alter their interaction with
ß3 tail peptides in cell lysates. Our results provide novel insight into
the molecular architecture and the phosphorylation dynamics in podosomes.
Moreover, they outline a novel potential mechanism for the recruitment of
paxillin and Pyk2 to ß3 integrin-dependent cell contacts.
Key words: Osteoclast, Podosome, Integrin, Cytoskeleton, Cell adhesion
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