Michael R. Freeman

Department of Surgery
Children's Hospital
Enders Building, Room 1161
300 Longwood Ave.
Boston, MA 02115
Tel: (617) 919-2644
Fax: (617) 730-0238
Email: Michael.freeman@childrens.harvard.edu
Web Page: The Freeman Lab Page
Administrative contact: Erica Thompson
Tel: (617) 919-2643
Email: erica.thompson@childrens.harvard.edu

My group focuses on studies directed toward understanding the molecular basis of genitourinary tract pathobiology, with a primary focus on mechanisms of signal transduction.

ErbB pathway signaling. We are investigating the function and regulatory mechanisms of the ErbB receptor tyrosine kinase ligand, heparin-binding EGF-like growth factor (HB-EGF), in a variety of cell and organ systems. The studies on HB-EGF/ErbB signaling center on three major areas:  (1) smooth muscle cell (SMC) growth regulation; (2) the regulation of prostate epithelial cell growth and survival; and (3) the role of HB-EGF as a nuclear-localized protein in aggressive bladder cancer. These studies have demonstrated that HB-EGF is an important regulatory protein in autocrine regulation of uroepithelial cells and hypertrophic muscle growth. We have also shown that the protein is a mediator of stromal to epithelial signaling and a functionally relevant cancer biomarker.  Most recently we are studying the mechanism of EGF receptor trafficking to nuclei and incorporation of the receptor into transcriptionally active chromatin.

Cholesterol-sensitive signal transduction. Another area involves the mechanisms of signal processing through the PI3K/Akt/mTOR signal transduction pathway in cancer. Recent studies from our group have implicated membrane cholesterol as an important regulatory element in this pathway [2,3]. The findings in prostate cancer suggest a link between cancer progression and a diet rich in fat and animal products, a relationship supported by recent epidemiological evidence.

Proteomics and biomarker discovery. Our laboratory is adjacent to the Proteomics Center at Children’s Hospital. We are using the state-of-the-art proteomics tools to study multi-protein complexes, particularly in the Akt signaling and EGF receptor trafficking pathways, and also for the purpose of discovering novel disease biomarkers.

References:

• Kim, J., Adam, R.M., and Freeman, M.R. (2005) Trafficking of nuclear HB-EGF into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Research 65:8242-8249.
• Zhuang, L., Kim, J., Adam, R.M., Solomon, K.R., and Freeman, M.R. (2005) Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. Journal of Clinical Investigation 115:959-968.
• Adam, R.M., Mukhopadhyay, N.K., Kim, J. Di Vizio, D., Cinar, B., Boucher, K., Solomon, K.R., and Freeman, M.R. (2007) Cholesterol sensitivity of endogenous and myristoylated Akt. Cancer Research (In press).
• Mukhopadhyay, N.K., Cinar, B., Mukhopadhyay, L., Lutchman, M., Ferdinand, A.S., Chung, L.W.K., Adam, R.M., Ray, S.K., Leiter, A.B., Richie, J.P., Liu, B. C.-S., and Freeman, M.R. (2007) The zinc finger protein RREB-1 is a co-regulator of the androgen receptor: Implications for the role of the Ras pathway in enhancing androgenic signaling in prostate cancer. Molecular Endocrinology (In press).