Kathrin H. Kirsch
Associate Professor of Biochemistry
Department of Biochemistry
Boston University School of Medicine
Silvio Conte Building, K-201
72 E. Concord Street
Boston, MA 02118
Phone: (617) 638-4376
Fax: (617) 638-5339
Email: kirschk@bu.edu
Education
Dipl.-Biol., Humboldt University, Berlin, Germany
Ph.D., Ludwig Maximilians University, Munich, Germany
Post-doctoral training, The Rockefeller University, New York, NY
Research Interests
My laboratory is working on delineating molecular mechanisms that are important for tumor initiation and progression, with a specific focus on the expanding family of cytoplasmic adapter proteins. Adapter proteins are integrally involved in the intracellular regulation of diverse signaling events. Variations in their distinct domains, and complex interactions with other molecules, endow the members of the adapter protein family with important roles in the control of cellular proliferation, differentiation, adhesion, and motility.
One of the key regulators in the control of growth and differentiation is the adapter protein p130Cas. Originally identified as a tyrosine-phosphorylated protein in transformed fibroblasts, p130Cas has subsequently been demonstrated to be a central element of the machinery that controls migration and invasive growth of tumor cells. This function has been underscored by the finding that aberrant expression of p130Cas correlates with poor prognosis in patients suffering from breast cancer and with resistance to antiestrogen therapy. We are currently investigating the participation of p130Cas in pathways of growth regulation in cancers of the mammary gland, and attempting to identify additional signaling molecules that associate with p130Cas. We have established a transgenic mouse model to investigate the role of p130Cas in normal mammary development and in breast cancer.
Recently we have identified another adapter, called CMS, which associates with the SH3 domain of p130Cas. This new member of the adapter protein family, named CMS/CIN85, contains multiple domains that mediate the assembly of larger protein complexes through a non-catalytic mechanism. We have demonstrated that CMS associates with other molecules that have an important role in intracellular signaling, such as Src-like tyrosine kinases, PI3-kinase, and the ubiquitin ligase c-Cbl. Moreover, we have found that the interaction between CMS and c-Cbl can be induced by specific growth factors, which facilitates receptor internalization. By extensive structure function analysis we recently revealed that CMS/CIN85 family proteins bundle F-actin and form heterotypic complexes. Dynamic cytoskeletal rearrangements are important in during development and adult physiology. Our current work with CMS is focused on its roles in growth factor signaling, in the processes of cell adhesion and movement, and in growth factor-mediated remodeling of the actin cytoskeleton. Our approaches include protein biochemistry, cell culture, and molecular genetics.
Representative Publications
Kirsch, K.H., M.-M. Georgescu, and H. Hanafusa. Direct binding of p130Cas to guanine nucleotide exchange factor C3G. J. Biol. Chem. (1998) 273:25673-25679.
Kirsch, K.H., M.-M. Georgescu, S. Ishimaru, and H. Hanafusa. CMS: An adapter molecule involved in cytoskeletal rearrangements. Proc. Natl. Acad. Sci. USA (1999) 96:6211-6216.
Kirsch, K.H., M.-M. Georgescu, T. Shishido, W. Y. Langdon, R. Birge and H. Hanafusa. The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl though a tyrosine phosphorylation-regulated Src homology 3 domain interaction. J. Biol. Chem. (2001) 276:4957-4963.
Kirsch K.H., M. Kensinger, H. Hanafusa, and A. August. A p130Cas tyrosine phosphorylated substrate domain decoy disrupts v-Crk signaling. (2002) BMC Cell Biol. 3:18
Wang X., K. Belguise, N. Kersual, K.H. Kirsch, N.D. Mineva, F. Galtier, D. Chalbos, and G.E. Sonenshein. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. (2007) 9:470-478
Gaidos G, S. Soni, D.J. Oswald, P.A. Toselli, and K.H. Kirsch. Structure and function analysis of the CMS/CIN85 protein family identifies actin-bundling properties and heterotypic-complex formation. J Cell Sci. (2007) 120:2366-77.
Min C, K.H. Kirsch, Y. Zhao, S. Jeay, A.H. Palamakumbura, P.C. Trackman, G.E. Sonenshein. The tumor suppressor activity of the lysyl oxidase propeptide reverses the invasive phenotype of Her-2/neu-driven breast cancer. Cancer Res. (2007) 67:1105-12.
Zhao, Y., C. Min, S. Vora, P.C. Trackman, G.E. Sonenshein, K.H. Kirsch*. The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of FAK and p130Cas in breast cancer cells. J. Biol. Chem (2009) 284: 1385-1393. PMID: 19029090
Soni, S., B.-T. Lin, A. August, R.I. Nicholson, K.H. Kirsch*. Expression of a phosphorylated p130Cas substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells. J. Cell. Biochem. (2009) 107:364-375. PMID: 19330798
Min C., Z. Yu, K.H. Kirsch, Y. Zhao, S.R. Vora, P.C. Trackman, D.B. Spicer, L. Rosenberg, J.R. Palmer and G.E. Sonenshein. A loss of function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer Res. (2009) 69:6685-6693. PMID: 19654310
Palamakumbura A.H., S.R. Vora, M.A. Nugent, K.H. Kirsch G.E. Sonenshein and P.C. Trackman. Lysyl Oxidase Pro-peptide Inhibits Prostate Cancer Cell Growth by Mechanisms that Include FGF-2 Cell Binding and Signaling. Oncogene. (2009) Jul 13. [Epub ahead of print]. PMID: 19597471
