Model representing the functions of cten and tensin-3 in promoting EGF-induced cell migration.

Epidermal growth factor receptor (EGFR) promotes normal cell migration but can also contribute to tumour invasion. It is known that EGFR activation alters gene expression; however, the identity of EGF-regulated genes affecting cell motility is still largely unknown. Yarden and colleagues now detail in Nature Cell Biology how changes in the expression of two members of the tensin family — tensin-3 and cten (C-terminal tensin-like protein) — may account for EGFR-induced cell migration.

Members of the tensin family of adaptor proteins regulate focal adhesions and cell migration. Whereas three of the four proteins described so far have a both C-terminal PTB domain that interacts with the cytoplasmic tail of integrins and an N-terminal domain that interacts with actin, the fourth member, cten, lacks the actin-binding domain. Yarden and colleagues analysed transcription profiles of EGF-treated HeLa cells and found reciprocal alterations in tensin-3 and cten expression, which are downregulated and upregulated respectively. They confirmed this in MCF10A mammary epithelial cells, and showed that protein levels mirror this shift.

Depletion of cten by short interfering RNA (siRNA) dramatically reduced EGF-induced mammary cell migration and restored a dense network of actin stress fibres. Conversely, tensin-3 depletion resulted in stress fibre disintegration and a slight increase in cell migration. These results suggest EGF-driven cell movement depends upon the induction of cten and is accompanied by actin cytoskeleton reorganization. Consistent with this, overexpression of cten caused extensive fibre disassembly.

How can changes in cten and tensin-3 expression levels alter cell behaviour? The integrity of resting epithelial tissues is maintained by actin stress fibres, which are stabilized by integrin-based focal adhesion sites. Tensin-3 mediates this stabilization by interacting simultaneously with actin and the cytoplasmic integrin tail. Yarden and colleagues propose that cten competes with tensin-3 for the cytoplasmic tail of integrins. When tensin-3 is replaced by cten, stress fibres disintegrate because cten lacks an actin-binding domain. In accordance with this model, the authors showed that cten requires a functional PTB integrin-binding domain to affect actin organization, and that overexpression of cten can displace tensin-3 from focal adhesion sites. EGFR activation then triggers two complementary processes to ensure dissociation of the integrin-tensin-actin complex and stress fibre disintegration: reduction of tensin-3 and upregulation of cten levels, which caps the tail of integrins.

Human breast cancer progression is often associated with aberrant upregulation of EGFR signalling. The authors analysed samples of invasive breast carcinomas and found a strong correlation between a tumour's ability to metastasize and the presence of cten. Furthermore, treatment of a small group of breast cancer patients with an EGFR kinase inhibitor showed that cten expression in breast cancers depends upon EGFR. Cten may therefore serve as a useful marker for EGFR-driven tumours, however, whether cten drives tumour invasion remains to be determined.

Author: Kim Baumann