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|Kathryn M. Eisenmann, Ph.D.
Biochemistry and Cancer Biology
The mammalian Diaphanous (mDia)-related formins are Rho GTPase effector proteins that have critical roles in diverse cellular activities, including actin and microtubule dynamics, gene transcription, cell cycle, and membrane trafficking. mDia proteins nucleate, processively elongate, and (in some cases) bundle nonbranched actin filaments. Other Rho GTPase effector proteins, such as those of the Wiskott-Aldrich Syndrome (WASp)/Scar family, indirectly promote actin assembly by stimulating the Arp2/3 complex to bind to pre-existing filaments and nucleate branched filaments.
Dia-interacting protein (DIP) interacts through an amino-terminal SH3 domain with N-WASp or with the related mDia family members mDia1 and mDia2 , Upon binding to N-WASp, DIP stimulates Arp2/3-mediated nucleation; DIP binds to and directly activates the Arp2/3 complex. DIP also bears a conserved C-terminal leucine-rich region (LRR) that can bind both mDia1 and mDia2.
I identified DIP as a negative regulator of mDia2-mediated actin filament assembly in vitro and in cells. DIP LRR not only inhibited mDia2 during filopodia assembly but also triggered non-apoptotic membrane blebbing. A physiologic process, membrane blebbing engages elements of the contractile machinery and is hypothesized to function in amoeboid cell movement (ACM). ACM has also recently been described as a specialized mode of breast cancer cell motility and is thought to play an essential role in metastasis. Though the specific components of the cellular machinery contributing to ACM have remained elusive, the control of mDia2 by DIP LRR in the induction of membrane blebbing suggests a role for these molecules in mediating ACM.
The molecular underpinnings of amoeboid cell movement in tumor cells have yet to be characterized. Dia-interacting protein (DIP), with its ability to act as a pivot between two types of actin nucleators and promote amoeboid-like blebbing, may critically control the mesenchymal-amoeboid transition (MAT) during directed three-dimensional breast cancer cell migration. Therapeutics targeting mesenchymal-type migration (i.e. metalloprotease inhibitors) have largely failed in clinic for the treatment of breast cancers suggesting that breast cancer cells may compensate by utilizing protease-independent mechanisms for cell migration and invasion. Understanding the role of DIP in controlling formin (de)activation and its affects on amoeboid cell movement may lend novel insight as to mechanisms controlling the transition towards amoeboid-based cell migration/invasion and metastasis of breast cancer cells and provide an alternate therapeutic avenue.
Member of the mentoring faculty for the Biomedical Sciences Graduate Program (Cancer Biology Track)
Ph.D. 2000 Molecular, Cellular, Developmental Biology & Genetics, University of Minnesota, Twin Cities
B.S. 1995 Biology, magna cum laude, Rider University, NJ
2008-present Assistant Professor, Biochemistry & Cancer Biology, University of Toledo College of Medicine,
2003-2008 Postdoctoral Fellow, Laboratory of Cell Structure & Signal Integration, Van Andel
Research Institute, Grand Rapids, MI
Eisenmann, K.M., Dykema, K.J., Matheson, S.F., Kent, N.F., DeWard, A.D., West, R.A., Tibes, R., Furge, K.A., and Alberts, A.S. 2010. 5q-myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics. Oncogene 28(39):3429-3441.
DeWard, A.D.*, Eisenmann, K.M.*, Matheson, S.F. and Alberts, A.S. 2010. The role of formins in human disease. Biochim Biophys Acta 1803(2):226-233. (*equal contributors)
Gupton, S., Eisenmann, K.M., Alberts, A.S., Waterman-Storer, C.L. 2007. mDia2 Regulates Actin Dynamics and Organization in the Lamella for Efficient Epithelial Cell Migration. J Cell Sci. 120 (Pt 19):3475-87.
Peng, J., Kitchen, S.M., West, R., D., Sigler, R., Eisenmann, K.M., and A.S. Alberts, A.S. 2007. Myeloproliferative Defects Following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous-related Formin mDia1. Cancer Research. 67(16): 7565-71.
Eisenmann, K.M., West, R.A., Hildebrand, D., Kitchen, S.M., Peng, J., Sigler, R., Zhang, J., Siminovitch, K., and A.S. Alberts. 2007. T cell responses in mammalian diaphanous-related formin mDia1 knockout mice. J. Biol. Chem. 282(34): 25152-8.
Eisenmann, K.M., Harris, E., Kitchen, S.M., Holman, H.A., Higgs, H.N., and A.S. Alberts. 2007. Dia-Interacting Protein Modulates Formin-Mediated Actin Assembly at the Cell Cortex. Current Biology. 17: 579-91.
Eisenmann, K.M., VanBrocklin, M., Staffend, N., Kitchen, S., and Koo, H-M. 2003. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein Bad. Cancer Research. 63:8330-8337.
Chen, R., Kim, O., Yang, J., Eisenmann, K.M., Sato, K., Chan, S., Tsichilis, P.N., McCarthy, J.B., Guan, J.L., and Qui, Y. 2001. Tyrosine phosphorylation is required for Akt Activation. J Biol Chem. 276: 31858-31862.
Eisenmann, K.M., McCarthy, J.B., Simpson, M.A., Keely, P.J., Guan, J.L., Tachibana, K., Lim, L., Manser, E., Furcht, L.T. and Iida, J. 1999. Melanoma chondroitin sulfate proteoglycan regulated cell spreading through Cdc42, Ack-1 and p130cas. Nature Cell Biology. 1:507-513.
Eisenmann, K.M., Peng, J., Wallar, B.J., and Alberts, A.S. 2004. Rho GTPase-Formin pairs in cytoskeletal
remodeling. 2005. Novartis Found Symp. 269: 206-216.