ShcA is a protein that is recruited to receptor-protein tyrosine kinases, where it is phosphorylated on several tyrosine residues. These phosphotyrosine residues act as binding sites for Grb2. Interestingly, some receptors also bind Grb2 directly, which would suggest a redundant role for ShcA. Recently, we demonstrated that cells expressing receptors engineered to bind ShcA display enhanced rates of cell division compared to cells expressing versions of the receptor designed to bind Grb2 directly. In this dissertation, I describe our efforts to identify and characterize novel ShcA-binding proteins that may play a role in this phenomenon. Chapter 1 is an introductory chapter that describes the field of receptor protein-tyrosine kinase signaling. Chapter 2 describes the use of ShcA-derived phosphopeptides as reagents to purify proteins that bind ShcA in a phosphorylation-dependent manner. This led to the identification of STS-1 as a protein that associates with the phosphorylated Tyr317 region of ShcA. In cell-based experiments, we demonstrate that the association between STS-1 and ShcA is enhanced following growth factor stimulation. In chapter 3, we demonstrate that STS-1 binds directly to the phosphorylated Tyr317 ShcA-derived peptide. To determine which region of STS-1 directly binds the peptide, two complementary approached were undertaken. In the first, purified STS-1 was subjected to limited proteolysis with thermolysin and the resulting fragments were incubated with the phosphorylated Tyr317 ShcA-derived peptide. A fragment that includes the region of STS-1 with homology to 2H phosphoesterases retained the ability to bind the peptide. In the second approach, mammalian cell lysates expressing STS-1 constructs with point mutations intended to disable individual domains of STS-1 were incubated the phosphorylated Tyr317 ShcA-derived peptide. STS-1 constructs with mutations in the domain with homology to 2HPEs failed to associate with the peptide. Chapter 4 describes the ability of STS-1 to dephosphorylate (or regulate dephosphorylation) of ShcA. We show that STS-1 can dephosphorylate tyrosine residues of ShcA in vitro. Additionally, we show that depletion of STS-1 results in enhanced ShcA tyrosine phosphorylation and enhanced Akt activation in mammalian cells. In summary, my results demonstrate that STS-1 binds directly to ShcA in a phosphotyrosine-dependent manner and that STS-1 may also be a physiologically relevant ShcA-phosphatase.