AP-1 Differentially Expressed Proteins Krp1 and Fibronectin Cooperatively Enhance Rho-ROCK-Independent Mesenchymal Invasion by Altering the Function, Localization, and Activity of Nondifferentially Expressed Proteins

Abstract

The transcription factor AP-1, which is composed of Fos and Jun family proteins, plays an essential role in tumor cell invasion by altering gene expression. We report here that Krp1, the AP-1 up-regulated protein that has a role in pseudopodial elongation in v-Fos-transformed rat fibroblast cells, forms a novel interaction with the nondifferentially expressed actin binding protein Lasp-1. Krp1 and Lasp-1 colocalize with actin at the tips of pseudopodia, and this localization is maintained by continued AP-1 mediated down-regulation of fibronectin that in turn suppresses integrin and Rho-ROCK signaling and allows pseudopodial protrusion and mesenchyme-like invasion. Mutation analysis of Lasp-1 demonstrates that its SH3 domain is necessary for pseudopodial extension and invasion. The results support the concept of an AP-1-regulated multigenic invasion program in which proteins encoded by differentially expressed genes direct the function, localization, and activity of proteins that are not differentially expressed to enhance the invasiveness of cells.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank J. Winnie and L. Meagher for their technical assistance and P. McHardy and M. O'Prey for assistance with microscopy.

We gratefully acknowledge Cancer Research U.K. for their financial support.