Disclosed are compositions and methods useful in the regulation of cell proliferation. The invention provides TGF-.beta. (transforming growth factor .beta.) and IGFBP-3 (insulin like growth factor binding protein 3) as ligands that engage LRP (low density lipoprotein receptor-related protein), heretofore known as T.beta.R-V (TGF-.beta. receptor V) and IGFBP-3 receptor, to effect a change in the phosphorylation and activation status of IRS (insulin receptor substrate) proteins. Compositions comprising TGF-.beta. or IGFBP-3 and LRP or IRS protein are useful in the inhibition of cell proliferation and in the treatment of various diseases associated with unregulated cell proliferation.