Role of extracellular matrix and Ras in regulation of glomerular epithelial cell proliferation

Signals from extracellular matrix (ECM) to growth factor receptors regulate glomerular epithelial cell (GEC) proliferation. Epidermal growth factor (E GF), basic fibroblast growth factor, hepatocyte growth factor (HGF), or thr ombin stimulated proliferation of GECs when the cells were adherent to coll agen matrices, but not plastic substratum. Furthermore, EGF, HGF, or thromb in activated p42 mitogen-activated protein (MAP) kinase In collagen-adheren t GECs, whereas activation was weak in GECs on plastic. To further examine the Interaction of ECM with the Ras-MAP kinase cascade, GECs were stably tr ansfected with a constitutively active Ras mutant (V(12)Ras). Low or modera te levels of V(12)Ras expression did not affect basal MAP kinase activity b ut, unlike parental GECs, in clones that express V(12)Ras, EGF was able to induce proliferation and activate MAP kinase when these cells were adherent to plastic. In parental and V(12)Ras-transfected GECs, MAP kinase activati on was inhibited by cytochalasin D. Thus, adhesion of GECs to ECM facilitat es proliferation and MAP kinase activation by mitogens acting via tyrosine kinase or nontyrosine kinase receptors. Activation of pathway(s) downstream of V(12)Ras supplants signals from ECM that enable proliferation. These si gnals may involve the actin cytoskeleton.