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Last Updated: 4/23/2010
| 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 childhood leukemia. One project studies a family of transmembrane tyrosine kinases, the EGF receptor and family members, 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. The kinase domain then translocates 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 (which the HER4 Cyt1 isoform stimulates) and proliferation (which is promoted by the HER4 Cyt2 isoform).
A second project investigates a novel transmembrane tyrosine kinase, Mer, cloned and sequenced in our lab. Mer is normally expressed in monocyte/macrophages 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 and how this relates to chemoresistance and clinical outcomes in childhood leukemia.
A third project began when we examined Mer downstream signaling in prostate cancer cells. Mer activated an intracellular tyrosine kinase, Ack1, which we have shown tyrosine phosphorylates the androgen receptor on Tyr267. This Ack-androgen receptor pathway stimulates proliferation, cell survival, and gene expression in an androgen-independent manner. We have created prostate specific, activated Ack, transgenic mice to study prostate neoplasia as a single transgene and in crosses with other genetically-engineered mice with prostate phenotypes.
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
