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Last Updated: 6/17/2008
| H. Shelton Earp, MD
Lineberger Professor and Director |  |
Research Interests
Our lab is interested in how signals from membrane receptors are transduced to the nucleus altering gene expression, cell shape, proliferation and differentiation. We are particularly interested in tyrosine-specific protein kinases in breast and prostate cancer, as well as lymphoma/leukemia. One project studies a family of transmembrane tyrosine kinases, the EGF receptor and related molecules, HER2, HER3 and HER4. We are trying to identify distinctive substrates and pathways for these receptors in order to understand how they produce functional differences; for example, in breast cancer cells, EGF receptor or HER2 activation stimulates growth, whereas HER4 activation triggers differentiation. The mechanism by which HER4 signals is highly unusual involving a ligand-dependent two-step proteolytic process that releases the receptors 80kDa intracellular tyrosine kinase domain into the cytoplasm followed by translocation to the nucleus. We have created mice with Doxycycline-inducible HER4 intracellular domains allowing us to study the isoform specific role of nuclear HER4 in differentiation and proliferation.
A second project investigates a novel transmembrane tyrosine kinase, Mer, cloned and sequenced in our lab. Mer is normally expressed in monocytes, as well as in epithelial and reproductive tissue (including prostate). It is not expressed in normal B or T lymphocytes. However, 60% of childhood lymphatic leukemias express Mer, including a subpopulation of childhood leukemias derived from very early T cell precursors. We have shown that Mer has anti-apoptotic and cytoskeletal regulatory actions. We are attempting to define the mechanism by which a tyrosine kinase sends anti-apoptotic signals without stimulating proliferation. Mer signaling also brings about Rac1 and cdc42 activation through a Vav-dependent process. Mer is expressed in prostate cancer and we are studying how signals downstream from Mer enhance prostate tumorigenesis. This has led to studies of a Mer-activated intracellular tyrosine kinase, Ack1. We are studying Ack-dependent (AR) androgen receptor tyrosine phosphorylate ion and its effect on AR-dependent gene expression, proliferation, survival, invasion and metastasis. We have created prostate specific, activated Ack, transgenic mice for future studies.
Publications
Use link below
E-mail: hse@med.unc.edu
Telephone: (919) 966-3036
FAX: (919) 966-3015
Address: Lineberger Comprehensive Cancer Center, 450 West Drive, CB 7295 Chapel Hill, NC 27599
