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Published online March 10, 2008
doi:10.1083/jcb.200708048
The Journal of Cell Biology, Vol. 180, No. 5, 957-971
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Cortesio et al.
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Article

 Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion

Christa L. Cortesio1,2,3, Keefe T. Chan2,3, Benjamin J. Perrin2,3, Nicholas O. Burton2,3, Sheng Zhang4, Zhong-Yin Zhang4, and Anna Huttenlocher2,3

1 Department of Biomolecular Chemistry, 2 Department of Medical Microbiology and Immunology, and 3 Department of Pediatrics, University of Wisconsin, Madison, WI 53706
4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202

Correspondence to A. Huttenlocher: huttenlocher{at}wisc.edu

Invasive cancer cells form dynamic adhesive structures associated with matrix degradation called invadopodia. Calpain 2 is a calcium-dependent intracellular protease that regulates adhesion turnover and disassembly through the targeting of specific substrates such as talin. Here, we describe a novel function for calpain 2 in the formation of invadopodia and in the invasive abilities of breast cancer cells through the modulation of endogenous c-Src activity. Calpain-deficient breast cancer cells show impaired invadopodia formation that is rescued by expression of a truncated fragment of protein tyrosine phosphatase 1B (PTP1B) corresponding to the calpain proteolytic fragment, which indicates that calpain modulates invadopodia through PTP1B. Moreover, PTP1B activity is required for efficient invadopodia formation and breast cancer invasion, which suggests that PTP1B may modulate breast cancer progression through its effects on invadopodia. Collectively, our experiments implicate a novel signaling pathway involving calpain 2, PTP1B, and Src in the regulation of invadopodia and breast cancer invasion.

Abbrevations used in this paper: ANOVA, analysis of variance; CCD, charge-coupled device; CII, compound II; ERK, extracellular signal-regulated kinase; FN, fibronectin; HEK, human embryonic kidney; pNPP, paranitrophenyl phosphate; PTP1B, protein tyrosine phosphatase 1B.


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