p38MAPK Induces Cell Surface alpha sub(4) Integrin Downregulation to Facilitate erbB-2-Mediated Invasion

We have previously shown that human breast cancer cells that overexpress erbB-2 are growth factor-independent. In order to test the contribution of erbB-2 to this and other transformed phenotypes without the genetic instability of cancer cells, erbB-2 was overexpressed in human mammary epithelial (HME) cells. ErbB-2-overexpressing HME cells exhibit several transformed phenotypes including cell surface alpha sub(4) integrin downregulation and invasiveness. We formulated a model for invasiveness that depends on a cell's ability to downregulate alpha sub(4) integrin. As small G-proteins play a role in cytoskeleton remodeling and as this is a likely route for alpha sub(4) integrin trafficking, we investigated the role of small G-proteins and their downstream signals in mediating alpha sub(4) integrin downregulation and invasiveness using Rac 1. Dominant-negative Rac 1 blocked erbB-2-mediated invasion and reversed erbB-2-mediated alpha sub(4) integrin downregulation. In addition, constitutively active Rac 1 induced alpha sub(4) integrin downregulation and invasiveness. In erbB-2-overexpressing and in constitutively active Rac 1-expressing cells, a p38MAP kinase (p38MAPK) inhibitor blocked invasiveness and reversed alpha sub(4) integrin downregulation. These data suggest a model in which erbB-2 signaling activates. Rac 1, which, in turn, activates p38MAPK, leading to the downregulation of alpha sub(4) integrin. These data strengthen the model where loss of alpha sub(4) integrin at the cell surface, leading to reduced alpha sub(4) integrin binding to plasma fibronectin, plays a role in erbB-2-mediated invasiveness.