The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.

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Podocyte damage is the basis of many glomerular diseases with ultrastructural changes and decreased expression of components of the slit diaphragm such as nephrin and podocin. Under physiological conditions it is likely that the slit diaphragm underlies permanent renewal processes to indemnify its stability in response to changes in filtration pressure. This would require constant reorganization of the podocyte foot process and the renewal of slit diaphragm components. Thus far, the mechanisms underlying the turnover of slit diaphragm proteins are largely unknown. In this manuscript we examined a mechanism of nephrin endocytosis via CIN85/Ruk L -mediated ubiquitination. We can demonstrate that the loss of nephrin expression and onset of the proteinuria in CD2AP ؊/؊ mice correlates with an increased accumulation of ubiquitinated proteins and expression of CIN85/Ruk L in podocytes. In cultured murine podocytes CD2AP deficiency leads to an early ubiquitination of nephrin and podocin after stimulation with fibroblast growth factor-4. Binding assays with different CIN85/Ruk isoforms and mutants showed that nephrin and podocin are binding to the coiled-coil domain of CIN85/Ruk L . We found that in the presence of CIN85/Ruk L , which is involved in down-regulation of receptor-tyrosine kinases, nephrin is internalized after stimulation with fibroblast growth factor-4. Interestingly, coexpression of CIN85/Ruk L with CD2AP led to a decreased binding of CIN85/Ruk L to nephrin and podocin, which indicates a functional competition between CD2AP and CIN85/Ruk L . Our results support a novel role for CIN85/Ruk L in slit diaphragm turnover and proteinuria.Podocytes are highly specialized epithelial cells that cover the outer surface of the glomerular capillary tuft. They distend primary processes that further subdivide in numerous interdigitating foot processes. These foot processes form a specialized intercellular junction called "slit diaphragm." Many studies have emphasized the critical role of the slit diaphragm for maintaining the selective filtration barrier of the glomerulus (1, 2). Several proteins of the slit diaphragm have been identified that participate in common signaling pathways (3-5). One of the major components is nephrin. Nephrin is a transmembrane adhesion protein of the Ig superfamily, encoded by NPHS1. Humans and mice lacking nephrin are born without intact slit diaphragms and develop massive proteinuria already in utero (6, 7). There is cumulating evidence that nephrin is a signaling receptor molecule; nephrin forms with podocin and Neph1 a protein complex within the lipid raft that structurally functions as a transmembrane receptor (8). The intracellular human nephrin C terminus has several putative tyrosine phosphorylation sites that can be phosphorylated by the Src kinase Fyn. This receptor complex has been shown to interact with several protein kinases including Fyn, Yes, and phosphatidylinositol 3-kinase as well as with several adaptor proteins like Nck, Grb2, 2 and Crk (9, 10). A scaffolding protein ...