Ndfip1 and Ndfip2 are related endosomal membrane proteins that bind to and activate members of the Nedd4 family of E3 ubiquitin ligases. These ligases in turn affect receptor tyrosine kinase signaling by ubiquitinating several key components of the signaling pathways. Here we investigate the role of the Ndfip proteins in EGF signaling. We show that they associate with the EGF receptor and PTEN, and control the ubiquitination and abundance of PTEN, c-Cbl, and Src family kinases. Ndfip2, but not Ndfip1, also binds to and is phosphorylated by Src and Lyn, and can act as a scaffold for Src phosphorylation of Ndfip1 and potentially other substrates. Depletion of Ndfip1 inhibits Akt activation in EGF-stimulated HeLa cells, stimulates activation of Jnk, and enhances cell multiplication. Thus Ndfip1 and Ndfip2 are physically and functionally associated with multiple components of the EGF signaling cascade, and their levels modulate the relative output of different signaling pathways.