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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/C1862    most recent 00118.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Craig, D. H. Articles by Basson, M. D. Search for Related Content PubMed PubMed Citation Articles by Craig, D. H. Articles by Basson, M. D.

EXTRACELLULAR MATRIX, CELL INTERACTIONS

-Actinin-1 phosphorylation modulates pressure-induced colon cancer cell adhesion through regulation of focal adhesion kinase-Src interaction

Departments of ¹Surgery, ²Anesthesiology, ³Anatomy and Cell Biology, John D. Dingell Veterans Affairs Medical Center, Wayne State University, and Karmanos Cancer Institute, Detroit, Michigan; and ⁴Department of Surgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey and the Cancer Institute of New Jersey, New Brunswick, New Jersey

Submitted 25 March 2007 ; accepted in final form 26 September 2007

Physical forces including pressure, strain, and shear can be converted into intracellular signals that regulate diverse aspects of cell biology. Exposure to increased extracellular pressure stimulates colon cancer cell adhesion by a β₁-integrin-dependent mechanism that requires an intact cytoskeleton and activation of focal adhesion kinase (FAK) and Src. -Actinin facilitates focal adhesion formation and physically links integrin-associated focal adhesion complexes with the cytoskeleton. We therefore hypothesized that -actinin may be necessary for the mechanical response pathway that mediates pressure-stimulated cell adhesion. We reduced -actinin-1 and -actinin-4 expression with isoform-specific small interfering (si)RNA. Silencing of -actinin-1, but not -actinin-4, blocked pressure-stimulated cell adhesion in human SW620, HT-29, and Caco-2 colon cancer cell lines. Cell exposure to increased extracellular pressure stimulated -actinin-1 tyrosine phosphorylation and -actinin-1 interaction with FAK and/or Src, and enhanced FAK phosphorylation at residues Y397 and Y576. The requirement for -actinin-1 phosphorylation in the pressure response was investigated by expressing the -actinin-1 tyrosine phosphorylation mutant Y12F in the colon cancer cells. Expression of Y12F blocked pressure-mediated adhesion and inhibited the pressure-induced association of -actinin-1 with FAK and Src, as well as FAK activation. Furthermore, siRNA-mediated reduction of -actinin-1 eliminated the pressure-induced association of -actinin-1 and Src with β₁-integrin receptor, as well as FAK-Src complex formation. These results suggest that -actinin-1 phosphorylation at Y12 plays a crucial role in pressure-activated cell adhesion and mechanotransduction by facilitating Src recruitment to β₁-integrin, and consequently the association of FAK with Src, to enhance FAK phosphorylation.

mechanical signaling; pressure; cancer