A hypothesis is proposed, based upon studies carried out with substratum attached cultured chick embryo fibroblasts and fibroblasts transformed with oncogenic viruses, that a cell regulates its rate of growth by a mechanism that involves controlling mitogen receptor activity, i.e. the number of specific surface receptors that combine with labeled insulin. Mitogen receptor activity decreases with an increase in cell density; it is increased by a protein- and RNA-synthesis dependent response to culturing in the absence of serum, or it is increased by an exposure or activation of sites produced by trypsin treatment. Virus-transformed cells are defective in their ability to regulate mitogen receptor activity in response to these environmental signals. The objectives of the proposed research are to quantitatively characterize: (a) The binding of non-suppressible insulin-like activity (NSILA) and other mitogens to substratum-attached CEF under conditions found to alter 125I-insulin binding: (b) NSILA and insulin binding to substratum attached DNA virus- and chemically transformed mammalian cells; and (c) NSILA and insulin bonding to plasma membrane isolated from these cells and rapidly growing normal tissues. As support for the hypothesis that rapidly growing cells have greater mitogen receptor activity, we will measure the quantity of perfused, labeled mitogen bound to the surface of intact, rapidly and slowly growing normal liver, hepatomas and sarcomas. In the event that this methodology proves unfeasible, labeled antibody directed against the receptors will be infused into slowly and rapidly growing normal and malignant tissues, plasma membrane isolated, and the quantity of specific binding determined. This last approach necessitates that we identify, isolate and characterize the mitogen receptor.