Kathrin H. Kirsch
Boston University School of Medicine
Silvio Conte Building, Office: K123C, Lab: K112
72 E. Concord Street
Boston, MA 02118
Lab Phone: 617-638-4342
Dipl-Biol, Humboldt University, Berlin, Germany
PhD, Ludwig Maximilians University, Munich, Germany
Post-doctoral Training: The Rockefeller University, New York, NY
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. We are investigating the participation of p130Cas family proteins in growth regulation in cancers of the mammary gland. We have developed a transgenic animal model expressing a dominant-interfering p130Cas to investigate the role(s) of this molecule in normal mammary development and in breast cancer in vivo induced by aberrant expression of ErbB and Src family tyrosine kinases. Recently we have identified another adapter that associates with the SH3 domain of p130Cas, named CD2AP/CMS. We have found that CD2AP associates with the ubiquitin ligase c-Cbl in response to growth factors stimulation, and with F-actin. Moreover, we showed that CD2AP forms heterotypic complexes with its family member CIN85, and that both molecules bundle F-actin in vitro. Our current work with CD2AP is focused on its roles in growth factor signaling, cell adhesion and migration, and in growth factor-mediated remodeling of the actin cytoskeleton. In a collaborative effort with Dr. Sonenshein and Dr. Trackman, we are working on elucidating the mechanism of action of lysyl oxidase (LOX) on inhibition of Ras-mediated transformation. We have demonstrated that the propeptide region of LOX attenuates Ras- and Her-2/neu-dependent breast cancers in vitro and in xenograft models. Studies are in the progress to elucidate the mechanism of this inhibition. Long-term goals are to determine the potential for use the propeptide or derivatives in treatment of patients with Her-2/neu or Ras-mediated breast disease.
- p130Cas acts as survival factor during PMA-induced apoptosis in HL-60 promyelocytic leukemia cells. Kumbrink J, Kirsch KH. Int J Biochem Cell Biol. 2013 Mar;45(3):531-5. doi: 10.1016/j.biocel.2012.12.017. Epub 2012 Dec 31.
- Blimp1 activation by AP-1 in human lung cancer cells promotes a migratory phenotype and is inhibited by the lysyl oxidase propeptide. Yu Z, Sato S, Trackman PC, Kirsch KH, Sonenshein GE. PLoS One. 2012;7(3):e33287. Epub 2012 Mar 15.
- Kumbrink, J and Kirsch K.H. Regulation of p130Cas/BCAR1 expression in tamoxifen sensitive and tamoxifen resistant breast cancer cells by EGR1 and NAB2. (2012) Neoplasia: 1-13.
- Kumbrink, J and Kirsch K.H. Targeting Cas family proteins as novel treatment for breast cancer, Breast Cancer – Current and Alternative Therapeutic Modalities. Esra Gunduz and Mehmet Gunduz (Ed.), InTech. (2011) ISBN: 978-953-307-776-5, 37-62.Targeting Cas Family Proteins as a Novel Treatment for Breast Cancer
- Sánchez-Morgan, N., Kirsch K.H.,Trackman, P.C. and Sonenshein, G.E. The Lysyl Oxidase Propeptide Interacts with the Receptor Protein Type Phosphatase-Kappa and Inhibits b-Catenin Transcriptional Activity in Lung Cancer Cells. Mol Cell Biol. (2011) 31:3286-3297
- Sato S., Trackman, P.C., Mäki, J., Myllyharju, J., Kirsch, K.H., and Sonenshein, G.E. The Ras Signaling Inhibitor LOX-PP Interacts with Hsp70 and c-Raf to Reduce Erk Activation and Transformed Phenotype of Breast Cancer Cells. Mol Cell Biol. (2011) 31:2683-2695.
- Min C., Zhao Y., Romagnoli M., Trackman P.C., Sonenshein G.E., and Kirsch K.H. Lysyl Oxidase Propeptide Sensitizes Pancreatic and Breast Cancer Cells to Doxorubicin-Induced Apoptosis. J Cell Biochem. (2010) 111:1160-1168.
- 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
- 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
- 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
- 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
- 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.
- 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.
- 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
- 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
- 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.-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, and H. Hanafusa. Direct binding of p130Cas to guanine nucleotide exchange factor C3G. J. Biol. Chem. (1998) 273:25673-25679.