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The Giovanni Armenise-Harvard Foundation Session 2: Signal Transduction Overview This portion of the symposium focused on various aspects of cell signaling in normal and cancer cells. Two papers concern a family of proto-oncogenes that code for enzyme-linked receptors needed for growth and development of cells in the epithelium and liver, one describes the actions of a versatile intracellular enzyme, and the final presentation examined a protein-protein interaction that exerts diverse effects on intracellular activity.
Hepatocyte growth factor receptors (HGFRs) are one branch of a sprawling family of receptor tyrosine kinases that has been extensively studied since the early 1980s. When HGFRs are activated by the binding of hepatocyte growth factor (HGF) or macrophage stimulating protein (MSP), they first change the shape of their own intracellular domain, then initiate a cascade of events that are crucial to the growth and differentiation of epithelial cells in normal and malignant tissues. This presentation focused on three structurally related tyrosine kinases that belong to the HGFR family. These are encoded by three proto-oncogenes-MET, RON and SEA-that have been extensively studied at Dr. Comoglioâs institution. (A proto-oncogene is the normal form of a gene that stimulates cell growth; abnormal changes can turn it into an oncogene that causes the runaway growth typical of cancer cells.) The researchers used transgenic mice to explore several aspects of proto-oncogene activity, including synthesis regulation and related phenotypes, binding, and the interaction between proto-oncogenes and other proteins that act as signal transducers. By discovering how activated HGFRs can transmit such a wide range of biological signals, the researchers hope to learn more about the malignant transformation of normal cells.
This report focused on the recent discovery of genes that are related to the proto-oncogenes MET, RON and SEA. The prototype member of this new group has been named SEX, and related genes have been dubbed SEP, OCT and NOV. The genes are expressed in the early development of fetal brain and kidney and are critical to the normal development of neuronal tissue. Like other members of the receptor tyrosine kinase clan, the newly identified genes code for large transmembrane proteins. These genes have cysteine-rich extracellular domains, and the DNA sequence of their cytoplasmic domains (the part of the protein that protrudes into the cell) is nearly identical in all the relatives of MET. Well-conserved sequences are thought to remain stable because they do something very important, and researchers are working to define what the function of this one might be. Future studies will also look for physical changes associated with elevated expression of these genes and to learn more about how they regulate development.
When a growth factor, hormone, or other stimulatory molecule binds to a receptor on the cell surface, a second messenger transduces the signal to the interior of the cell. Second messengers are formed when one of two enzymes-either phospholipase C or phosphoinositide 3-OH kinase (usually referred to as PI (3)-kinase)-alters the phospholipids found in the membrane itself. In different types of cells, the PI (3)-kinase signaling pathway is activated by different growth factor receptors or hormones. The types of proteins that PI (3)-kinase interacts with depends on the cell type, and the varied nature of these proteins may help explain how the PI (3) K enzymes regulate so many diverse functions. These include the survival, transformation and movement of cells, in addition to intracellular trafficking.
Small protein modules that are made and folded independently often join together to form larger proteins that have important jobs to do. Dr. Di Fiore and his colleagues recently identified a new protein-protein interaction domain, located on two signal transducer proteins, eps15 and eps15R, as well as on other yeast and nematode proteins. They call this protein-protein interaction site EH (for Eps15 homology). In laboratory experiments, the researchers found that EH domains from eps15 and eps15R bind to peptides containing the asparagine-proline-phenylalanine (NPF) motif. When they used EH domains to screen expression libraries, they found a number of putative EH interactors including the human homologue of NUMB, a developmentally regulated gene of Drosophila, and RAB, the cellular cofactor of ReV, a regulatory protein in HIV-1. Each of these interactors possessed the crucial NPF motif. Analysis of these findings suggests that that EH domains are involved in the transport and sorting of molecules within the cell, including cell trafficking, cytoskeleton organization, endocytosis and vesicle recycling.
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The HGF receptor family
