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Endocytosis is a regulated physiological process by which cell surface proteins are internalized along with extracellular factors such as nutrients, pathogens, peptides, toxins, etc. The process begins with the invagination of small regions of the plasma membrane which ultimately form intracellullar vesicles. These internalized vesicles may shuttle back to the plasma membrane to recycle the membrane components or they may be targeted for degradation. One role for endocytosis is in the attenuation of receptor signaling. For example, desensitization of activated membrane bound receptors such as G-protein coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs) occurs, in part, through endocytosis of the activated receptor. However, accumulating evidence suggests that endocytosis also mediates intracellular signaling. In this review, we discuss the experimental data that implicate endocytosis as a critical component in cellular signal transduction, both in the initiation of a signal as well as in the termination of a signal. Furthermore, we focus our attention on a recently described adaptor protein, intersectin (ITSN), which provides a link to both the endocytic and the mitogenic machinery of a cell. Thus, ITSN functions at a crossroad in the biochemical regulation of cell function.

Genetic alterations are involved in the development of human breast cancer. We sought to isolate genes that are differentially expressed or suppressed in cultured human breast carcinoma cells as compared to cultured normal human breast epithelial cells by employing differential screening of selected cDNA libraries. Analysis of several clones thus isolated revealed that the matrix Gla protein (MGP) gene is overexpressed in the breast cancer cell line 600 PEI, though is transcribed at lower levels in most other mammary derived cultures. MGP requires vitamin K dependent gamma-carboxylation for its known function and thus can be inhibited by vitamin K antagonists. This raises the possibility that MGP may be among those factors that when inhibited by vitamin K antagonists reduce metastases in experimental models. Among the gene whose transcription is consistently suppressed upon mammary transformation were fibronectin and the type I keratin, K14. Differential cDNA screening therefore is an effective method of identifying genes involved in various aspects of mammary cell transformation.