Integrin β4 Regulates SPARC Protein to Promote Invasion*
- Kristin D. Gerson‡,
- Jeffrey R. Shearstone‡,
- V. S. R. Krishna Maddula§,
- Bruce E. Seligmann§ and
- Arthur M. Mercurio‡,1
- From the ‡Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
- §High Throughput Genomics, Inc., Tucson, Arizona 85706
- ↵1 To whom correspondence should be addressed: Dept. of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.
Abstract
The α6β4 integrin (referred to as “β4” integrin) is a receptor for laminins that promotes carcinoma invasion through its ability to regulate key signaling pathways and cytoskeletal dynamics. An analysis of published Affymetrix GeneChip data to detect downstream effectors involved in β4-mediated invasion of breast carcinoma cells identified SPARC, or secreted protein acidic and rich in cysteine. This glycoprotein has been shown to play an important role in matrix remodeling and invasion. Our analysis revealed that manipulation of β4 integrin expression and signaling impacted SPARC expression and that SPARC facilitates β4-mediated invasion. Expression of β4 in β4-deficient cells reduced the expression of a specific microRNA (miR-29a) that targets SPARC and impedes invasion. In cells that express endogenous β4, miR-29a expression is low and β4 ligation facilitates the translation of SPARC through a TOR-dependent mechanism. The results obtained in this study demonstrate that β4 can regulate SPARC expression and that SPARC is an effector of β4-mediated invasion. They also highlight a potential role for specific miRNAs in executing the functions of integrins.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant CA80789 (to A. M. M.). This work was also supported by Department of Defense Breast Cancer Fellowship BC100607 (to K. D. G.). Bruce Seligmann works in a leadership role for, and owns stock in, HTG, Inc., the company that produces and markets the qNPA assay. He has no affiliation with, nor does he consult with, the University of Massachusetts. This work was carried out using funds from the Arizona Science Foundation through a grant to the University of Arizona, David Galbraith, PI, for which HTG is the industry collaborator. Krishna Maddula works as a postdoctoral fellow for, and owns stock in, HTG, Inc., the company that produces and markets the qNPA assay. He has no affiliation with, nor does he consult with, the University of Massachusetts.
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This article contains supplemental Experimental Procedures, Fig. S1, and Tables S1 and S2.
- Received October 31, 2011.
- Revision received December 22, 2011.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
