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First published online 11 March 2003
doi: 10.1242/jcs.00386
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Research Article |
1 Department of Oral Biology, College of Dentistry, University of Nebraska
Medical Center, Lincoln, NE 68583, USA
2 University of Minnesota Cancer Center, Minneapolis, MN 55455, USA
3 Department of Laboratory Medicine and Pathology, Minneapolis, MN 55455,
USA
4 Department of Orthopaedic Surgery, Minneapolis, MN 55455, USA
5 Eppley Institute for Research in Cancer and Allied Diseases, Department of
Biochemistry and Molecular Biology, and Department of Pathology and
Microbiology, University of Nebraska Medical Center, Omaha, NE 68198,
USA
* Author for correspondence (e-mail: weste047{at}umn.edu)
Accepted 23 January 2003
Formin-homology-domain-containing proteins interact with Rho-family GTPases
and regulate actin cytoskeleton organization and gene transcription. FHOD1 is
a member of this family, interacts with Rac1 and induces transcription from
the serum response element. In this study, we examined the effects of FHOD1
expression on cytoskeletal organization and function in mammalian cells. FHOD1
proteins were stably expressed in WM35 melanoma cells and NIH-3T3 fibroblasts.
Cells expressing full-length FHOD1 demonstrated an elongated phenotype
compared with vector-transfected cells and cells expressing a truncated FHOD1
(1-421) that lacks the conserved FH1 and FH2 domains. Full-length FHOD1
co-localized with filamentous actin at cell peripheries. Cells transiently
expressing a C-terminal FHOD1 truncation mutant (
C, residues 1-1010),
which lacks an autoinhibitory protein-protein interaction domain, displayed
prominent stress fibers. FHOD1 (1-421) did not induce stress fibers but
localized to membrane ruffles in a manner similar to the full-length protein,
indicating that the FH1 and FH2 domains are required for stress fiber
appearance. FHOD1 C (1-1010)-dependent stress fibers were sensitive to
dominant-negative RacN17 and the RhoA and ROCK inhibitors, C3 transferase and
Y-27632. Stable overexpression of full-length FHOD1 enhanced the migration of
WM35 and NIH-3T3 cells to type-I collagen and fibronectin, respectively. Cells
expressing FHOD1 (1-421) migrated similar to control cells. Integrin
expression and activation were not affected by FHOD1 expression. Moreover,
FHOD1 overexpression did not alter integrin usage during adhesion or
migration. These data demonstrate that FHOD1 interacts with and regulates the
structure of the cytoskeleton and stimulates cell migration in an
integrin-independent manner.
Key words: Formin homology, FHOD1, Actin cytoskeleton, Stress fibers, Migration, Cell motility, FHOS
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