p38MAPK Induces Cell Surface α4 Integrin Downregulation to Facilitate erbB-2-Mediated Invasion

AbstractWe have previously shown that human breast cancer cells that overexpress erbB-2 are growth factorindependent. In order to test the contribution of erbB2 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 α4 integrin downregulation and invasiveness. We formulated a model for invasiveness that depends on a cell's ability to downregulate α4 integrin. As small G-proteins play a role in cytoskeleton remodeling and as this is a likely route for α4 integrin trafficking, we investigated the role of small G-proteins and their downstream signals in mediating α4 integrin downregulation and invasiveness using Rac 1. Dominant-negative Rac 1 blocked erbB-2-mediated invasion and reversed erbB2-mediated α4 integrin downregulation. In addition, constitutively active Rac 1 induced α4 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 α4 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 α4 integrin. These data strengthen the model where loss of α4 integrin at the cell surface, leading to reduced α4 integrin binding to plasma fibronectin, plays a role in erbB-2-mediated invasiveness