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Published online 21 April 2003. doi:10.1083/jcb.jcb.200302126
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© The Rockefeller University Press, 0021-9525/2003/4/393 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 393-402

Article

 FAK induces expression of Prx1 to promote tenascin-C–dependent fibroblast migration

David M. McKean1, Lila Sisbarro1, Dusko Ilic3, Nihal Kaplan-Alburquerque2, Raphael Nemenoff2, Mary Weiser-Evans1, Michael J. Kern4 and Peter Lloyd Jones1

1 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262
2 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262
3 Department of Stomatology, University of California, San Francisco, San Francisco, CA 94143
4 Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425

Address correspondence to Peter L. Jones, Dept. of Pediatrics, University of Colorado Health Sciences Center, 4200 East 9th Ave., B-131, Denver, CO 80262. Tel.: (303) 315-4497. Fax: (303) 315-1326. E-mail: Peter.Jones{at}UCHSC.edu

Fibroblast migration depends, in part, on activation of FAK and cellular interactions with tenascin-C (TN-C). Consistent with the idea that FAK regulates TN-C, migration-defective FAK-null cells expressed reduced levels of TN-C. Furthermore, expression of FAK in FAK-null fibroblasts induced TN-C, whereas inhibition of FAK activity in FAK–wild-type cells had the opposite effect. Paired-related homeobox 1 (Prx1) encodes a homeobox transcription factor that induces TN-C by interacting with a binding site within the TN-C promoter, and it also promotes fibroblast migration. Therefore, we hypothesized that FAK regulates TN-C by controlling the DNA-binding activity of Prx1 and/or by inducing Prx1 expression. Prx1–homeodomain binding site complex formation observed with FAK–wild-type fibroblasts failed to occur in FAK-null fibroblasts, yet expression of Prx1 in these cells induced TN-C promoter activity. Thus, FAK is not essential for Prx1 DNA-binding activity. However, activated FAK was essential for Prx1 expression. Functionally, Prx1 expression in FAK-null fibroblasts restored their ability to migrate toward fibronectin, in a manner that depends on TN-C. These results appear to be relevant in vivo because Prx1 and TN-C expression levels were reduced in FAK-null embryos. This paper suggests a model whereby FAK induces Prx1, and subsequently the formation of a TN-C–enriched ECM that contributes to fibroblast migration.

Key Words: ECM; homeobox genes; adhesion; FAK-null; transcription

* Abbreviations used in this paper: EMSA, electrophoretic mobility shift assay; FN, fibronectin; FRNK, FAK-related nonkinase; HBS, homeodomain binding site; Prx1, paired-related homeobox 1; rPrx1, rat Prx1; TN-C, tenascin-C.


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