MERIT Award Recipient: Benjamin G. Neel, M.D., Ph.D.
|Sponsoring NCI Division:||Division of Cancer Biology (DCB)|
|Award Approved:||February 2004|
|Institution:||Beth Israel Deaconess Medical Center, Harvard University|
|Department:||Medicine, Cancer Biology Program|
|Benjamin G. Neel, M.D., Ph.D.|
Literature Search in PubMed
Signal Transduction by Non-transmembrane PTPs
One of the most important mechanisms by which cells receive and decode signals from the outside world is by adding or removing phosphate from specific tyrosine amino acids in cellular proteins, which alters the functions of the modified proteins. This process, known as protein-tyrosine phosphorylation, is regulated by enzymes that add phosphate, termed protein-tyrosine kinases (PTKs), or remove it (protein-tyrosine phosphatases; PTPs). Much is known about the roles of specific PTKs. For example, the receptors for most cellular growth factors and some hormones are PTKs that span the cell membrane ("receptor PTKs"). Most cytokine receptors and other immune-regulatory receptors also associate with and signal by activating intracellular PTKs.
Not surprisingly, genetic alterations in several PTKs are implicated in human disease. For example, the receptor PTK Her-2/Neu is amplified and over-expressed in about 30% of human breast and ovarian cancers and is the target for the drug Herceptin. In addition, specific chromosomal rearrangements can result in the generation of fusion proteins that activate other PTKs. The best-known example of this is the Philadelphia chromosome translocation, which leads to the generation of the BCR/ABL fusion protein, the cause of chronic myelogenous leukemia (CML). Gleevec, an inhibitor of this fusion protein, has had a profound impact on CML therapy. Other PTKs can be activated by genetic single point mutations, and are targets for drugs in clinical development; examples of this category include mutations in PTKs that cause developmental (e.g., dwarfism, piebaldism) and/or metabolic (e.g., diabetes) disorders.
Far less is known about the functions of PTPs in either normal physiology or disease. Like the PTKs, PTPs comprise a large gene family that encodes both cell surface (receptor-like) and intracellular (non-transmembrane) proteins. Dr. Neel and his colleagues study a particular non-transmembrane PTP, termed Shp2, which they identified in 1992. Work in several laboratories, including the Neel lab, has led to the initially surprising finding that the Shp2 PTP is required for signaling by receptor PTKs, as well as for signaling by cytokine receptors and immune-regulatory receptors. Moreover, very recent work has shown that specific Shp2 mutations are the cause of certain rare forms of leukemia as well as the most common human autosomal dominant genetic disease, Noonan syndrome.
Understanding the normal mechanism of action of Shp2 and how disease-associated Shp2 mutations perturb its function are the main goals of Dr. Neel's research program. To address these issues, he and his laboratory members take a combined biochemical, cell biological, and genetic approach. They have used mouse genetic techniques to make a mouse model for a specific Noonan syndrome mutation; these mice display nearly all of the features of the human disease. They have generated a large number of Shp2 mutant proteins and are studying their biochemical properties. They also are screening various forms of human tumors for Shp2 mutations. Finally, they have found that at least one way Shp2 acts to enhance receptor PTK signaling is by promoting the activation of a set of intracellular PTKs known as Src family kinases. Research supported by this MERIT Award will attempt to elucidate the molecular details of this regulatory mechanism.