The Faculty

Focus

MAPK signaling in cell differentiation, novel chemical probes of cell signaling

Education

Ph.D., Massachusetts Institute of Technology, 1978

Research Summary

Growth factor-mediated signal transduction is a process that is of fundamental importance in understanding cellular growth and differentiation. In recent years, a number of laboratories including my own have devoted considerable effort toward elucidating the mechanisms by which initiation of signal transduction by growth factors is regulated. We have focused many of our recent studies on the mechanisms by which the epidermal growth factor (EGF) receptor is regulated, with particular emphasis on heterologous regulation of exogenous growth modulators such as novel tumor promoters, retinoids and transforming growth factor-beta. Depending on the agent, this type of regulation can be stimulatory at the level of genetic expression of the receptor, or inhibitory at the level of biochemical regulation of receptor activity. During the past few years we have been isolating and characterizing the enzymes involved in the EGF signal transduction cascade, which are also important in the regulation of the EGF receptor itself. We have also investigated a number of growth modulators that alter transcription of the EGF receptor, and we have identified the domains within the EGF receptor promoter that are important for regulation by these agents. In addition, we have cloned, expressed and characterized a growth factor protease for transforming growth factor-alpha and insulin-related factors from both human and Drosophila sources that is highly conserved evolutionarily. This enzyme is a member of a newly emerging family of metalloproteinases that act as processing enzymes in species ranging from yeast to man. We plan to use this system to address the important problem of regulation of signal transduction by proteolytic degradation. Finally, we have focused our most recent efforts on elucidation of the signal transduction cascades leading to the differentiation of neuronal cells. Using conditionally immortalized CNS cell lines that we have generated, we have demonstrated that EGF stimulates growth but not differentiation of the cells, whereas fibroblast-derived growth factor can induce neuronal differentiation at the nonpermissive temperature. We are currently characterizing the kinase cascade leading to neuronal differentiation by growth factors and cloning novel genes that are regulated by this process.

Related interests:

  • Apoptosis
  • Cell Differentiation/Development
  • Signal Tranduction

Selected Papers

Abe, M.K., Kahle, K.T., Orth, K., Dixon, J.E. and Rosner, M.R. ERK7 is an Autoactivated Member of the MAP Kinase family.  J. Biol. Chem., 276 (24). 21272-21279. (2001)

Qian, Z., Lin, C., Espinosa, R., LeBeau, M., and Rosner, M.R.  Cloning and Characterization of MST4, a novel Ste20-like kinase.  J. Biol. Chem., 276 (25), 22439-22445.  (2001)

Abe, M.K., Saelzler, M.P., Espinosa III, R., Kahle, K.T., Hershenson, M.B., LeBeau, M.M., and Rosner, M.R., ERK8, a New Member of the MAP Kinase Family.  J. Biol. Chem., 277 (19) 16733-43. (2002)

Corbit, K.C., Trakul, N., Clark, M.C., Eves, E.M., Diaz, B., Marshall, M., Rosner, M.R., Activation of Raf-1 Signaling by Protein Kinase C Through a Mechanism Involving Raf Kinase Inhibitory Protein,  J. Biol. Chem.,  278 (15), 13061-13068,  (2003) (19) 16733-43. (2002)

Liu, J., Yang, D., Minemoto, Y., Leitges, M., Rosner, M.R., and Lin, A., NF-kB is required for UV-Induced JNK Activation via Induction of PKC, Molecular Cell, 21, 467-480. (2006)

Eves, E.M.,  Shapiro, P., Naik, K., Klein, U.R., and Rosner, M.R., Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Molecular Cell, 23, 561-574.  (2006)

Cohen, E.E.W., Zhu, H., Lingen, M.W., Martin, L.E., Kuo, W.-L., Choi, E.A., Kocherginsky, M., Parker, J.S., Chung, C.H., and Rosner, M.R., A Feed Forward Loop Involving Protein Kinase C Alpha and MicroRNAs Regulates Tumor Cell Cycle, Cancer Res.  69(1) 65-74. (2009)  Cell Cycle Features – Invited. PMCID: PMC2746005

Dangi-Garimella, S., Yun, J., Newman, M., Hammond, S. M., Eves, E.M., Minn, A.J. and Rosner, M.R. Raf Kinase Inhibitory Protein suppresses a metastasis signaling cascade involving LIN28 and let-7, EMBO J. 28(4), 347-58. (2009) PMCID: PMC2646152

Granovsky, A., Clark, MC, McElheny, D., Heil, G., Shiu, S-H, Hong, J., Liu, X., Kim, Y., Joachimiak, G., Joachimiak, A., Koide, S. and Rosner, M.R. Raf Kinase Inhibitory Protein is Regulated via a Flexible Pocket and Novel Phosphorylation-dependent Mechanism, Mol. Cell Biol., 29(5), 1306-20.  (2009) PMCID: PMC2643833

Shemon, A.N., Eves, E.M., Clark, M.C., Heil, G., Granovsky, A., Zeng, L., Imamoto, A.,Koide, S., and Rosner, M.R., Raf Kinase Inhibitory Protein Protects Cells against Locostatin-mediated Inhibition of Migration.  PLoS ONE.  4(6), e6028.  (2009) PMCID: PMC2696091

Doebele, R.C., Schulze-Hoepfner, F.T., Hong, J., Chlenski, A., Zeitlin, B.D., Goel, K., Gomes, S., Liu, Y., Abe, M., Nor, J.E., Lingen, M.W., and Rosner, M.R., A Novel Interplay Between Epac/Rap1 and MEK5/ERK5 Regulates Thrombospondin to Control Angiogenesis, Blood, 114(20):4592-600. (2009) PMCID: PMC2777131

Yun, J., Frankenberger, C.A., Kuo, W.-L., Boelens, M.C., Eves, E.M., Cheng, N., Liang, H., Li, W.-H., Ishwaran, H., Minn, A.J., and Rosner, M.R., Signaling Pathway for RKIP and Let-7 Regulates and Predicts Metastatic Breast Cancer, EMBO J, 30(21):4500-14, (2011)  PMC3230370.

Frank, S.A., and Rosner, M.R., Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer. PLoS Biology, 10(4):e1001296. Epub. (2012) PMCID: PMC3317895

Menon, J., Doebele, R.C., Gomes, S., Bevilacqua, E., Reindl, K.M., Rosner, M.R., A novel interplay between Rap1 and PKA regulates induction of angiogenesis in prostate cancer, PLoS One, 7(11):e49893, (2012) PMC3499522

Zeng, L., Ehrenreiter, K., Menon, J., Menard, R., Kern, F., Nakazawa, Y., Bevilacqua, E., Imamoto, A., Baccarini, M., Rosner, M.R., RKIP regulates MAP kinase signaling in cells with defective B-Raf activity, Cell Signal, doi:pii: S0898-6568(13)00045-4. 10.1016/j.cellsig.2013.02.005. PMC3622756