Department of Medicine
Director, Lineberger Comprehensive
- EGF receptor family
- HER4/ErbB4: growth inhibition and differentiation – Breast Cancer
- Mer receptor tyrosine kinase signaling – Leukemia and Tumor Immunology
- Ack1 receptor tyrosine kinase signaling – Prostate Cancer
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 activation of specific HER4 isoforms triggers differentiation. We have developed HER4 isoform specific, Tet inducible mouse models with which to study HER4’s disparate actions.
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 and how it results in chemoresistance in leukemia and other cancer cells. We are collaborating with Stephen Frye to develop small molecule, Mer TK inhibitors as in vivo chemical biologic probes and eventually as drugs for childhood leukemia. We are also investigating the role of Mer in tumor associated macrophages and their role in breast cancer.
Lastly, we have shown that Mer and other RTKs can activate an intracellular tyrosine kinase, Ack1. In turn, Ack1 tyrosine phosphorylates the androgen receptor (AR) on tyrosine 267, converting the AR into an androgen independent transcription factor. Ack1 activation leads to enhanced, androgen independent cell line tumorigenesis as well as invasion. We have shown that transgenic mouse models expressing activated Ack develop prostate neoplasia. We are defining the substrates and biologic actions that mediate Ack1-dependent cell survival and invasive behaviors.
Click above for PubMed publications.
- Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA Jr, McCall W, Sgagias MK, Cowan KH, Earp HS 3rd. Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Mol Cell Biol. 2006 Sep:26(17):6412-24. PMCID: PMC1592831.
- Feng SM, Sartor CI, Hunter D, Zhou H, Yang X, Caskey LS, Dy R, Muraoka-Cook RS, Earp HS 3rd. The HER4 cytoplasmic domain, but not its C terminus, inhibits mammary cell proliferation. Mol Endocrinol. 2007 Aug;21(8):1861-76. Epub 2007 May 15.
- Strunk KE, Husted C, Miraglia LC, Sandahl M, Rearick WA, Hunter DM, Earp HS 3rd, Muraoka-Cook RS. HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4. Cancer Res. 2007 Jul 15;67(14):6582-90.
- Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS 3rd. Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation. Mol Endocrinol. 2008 Oct;22(10):2307-21. Epub 2008 Jul 24. PMCID: PMC2582536.
- Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS 3rd. The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation. Mol Cell Biol. 2009 Feb;29(3):892-906. Epub 2008 Dec 1. PMCID: PMC2630679.
- Muraoka-Cook RS, Sandahl MA, Strunk KE, Miraglia LC, Husted C, Hunter DM, Elenius K, Chodosh LA, Earp HS 3rd. ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo. Mol Cell Biol. 2009 Sep;29(18):4935-48. Epub 2009 Jul 13. PMCID: PMC2738276.
- Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol. 1999 Mar 15;162(6):3498-503.
- Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, Earp HS, Matsushima GK. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001 May 10;411(6834):207-11.
- Guttridge KL, Luft JC, Dawson TL, Kozlowska E, Mahajan NP, Varnum B, Earp HS. Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. J Biol Chem. 2002 Jul 5;277(27):24057-66. Epub 2002 Apr 2.
- Mahajan NP, Earp HS. 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. 2003 Oct 24;278(43):42596-603. Epub 2003 Aug 14.
- Graham DK, Salzberg DB, Kurtzberg J, Sather S, Matsushima GK, Keating AK, Liang X, Lovell MA, Williams SA, Dawson TL, Schell MJ, Anwar AA, Snodgrass HR, Earp HS. Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clin Cancer Res. 2006 May 1;12(9):2662-9.
- Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35-83.
- Gregory CW, Whang YE, McCall W, Fei X, Liu Y, Ponguta LA, French FS, Wilson EM, Earp HS 3rd. Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res. 2005 Mar 1;11(5):1704-12.
- Mahajan NP, Whang YE, Mohler JL, Earp HS. Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res. 2005 Nov 15;65(22):10514-23.
- Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci USA. 2007 May 15;104(20):8438-43. Epub 2007 May 9. PMCID: PMC1895968.
- Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS, Whang YE. Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 2010 Jun 3;29(22):3208-16. Epub 2010 Apr 12. PMCID: PMC2880659.
Office Location: Mailing Address: Office Phone: 919-966-3036
Office Phone: 919-966-3036