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. Our prostate cancer projects examine how tyrosine kinase and androgen receptor signaling interrelate.
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 when expressed in mouse leukemic cell lines. 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..
Recent Publications:
Liu, Y., Majumder, S., McCall, W., Sartor, C.I., Mohler, J.L., Gregory, C.W., Earp, H.S., and Whang, Y.E. (2005) Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res 65(8): 3404-9. Abstract
Gregory, C.W., Whang, Y.E., McCall, W., Fei, X., Liu, Y., Ponguta, L.A., French, F.S., Wilson, E.M., and Earp, H.S. 3rd. Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 11(5): 1704-12. Abstract
Mahajan, N.P., and Earp, H.S. (2003) An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. J Biol Chem 278: 42596-603. Abstract
Guttridge, K.L., Luft, J.C., Dawson, T.L., Kozlowska, E., Mahajan, N.P., Varnum, B., and Earp, H.S. (2002) Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architechture without stimulation or proliferation. J Biol Chem 277(27): 24057-24066. Abstract
Sartor, C.I., Zhou, H., Kozlowska, E., Guttridge, K., Kawata, E., Calvo, E., Caskey, L., Harrelson, J., Hynes, N., Ethier, S., Calvo, B., and Earp, H.S. (2001) HER4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol 21: 4265-4275. Abstract
Scott, R.S., McMahon, E.L., Pop, S., Reap, E.A., Caricchio, R., Cohen, P.L., Earp, H.S., and Matsushima, G.K. (2001) Phagocytosis and clearance of apoptotic cells is mediated by Mer Nature 411: 207-211. Abstract
