Biology 260 (formerly 221) Cell and Molecular Biology
Biology/BMED 600 Cell Organization and Mechanisms
B.A. Kalamazoo College, 1978
Ph.D. University of Oregon, 1986
Multiple signals determine cell fates such as cell birth, death, and differentiation during development and in adult multicellular organisms. A major challenge in biology is to understand how signals from different receptors are integrated to determine an appropriate response. This process is particularly complicated in migrating cells such neurons and neural crest cells, and may go awry, resulting in increased cell proliferation or migration in cancer.
Neuroblastoma cell lines provide a model system to study the molecular mechanisms involved in sorting and transactivation between receptors. Many receptors signal from endosomes: to amplify signals, activate different effectors than those activated at the plasma membrane, or convey signals to different intracellular locations. There is evidence that endosomal signaling from a number of different receptors affects cell fate decisions during development. We hypothesize that multiprotein complexes of activated receptors and their effectors in endosomes play a role in signal integration when more than one receptor is activated.
We have shown that three different types of receptors are localized predominately in endosomes that are resolved from one another using a high-resolution organelle fractionation method based on mass and density (McCaffrey, et al., 2009). The data suggest that receptor sorting into specific signaling endosomes affects the compartmentalization of signaling pathways. The two receptors for nerve growth factor (NGF), TrkA and p75NTR, are rapidly sorted upon ligand binding to distinct endosomes. We have recently shown that sorting of these two receptors away from one another involves dynamic interactions between detergent-insoluble lipid rafts and microtubules (Pryor, et al., 2012). NGF caused TrkA to be attracted to lipid rafts, and p75NTR to sort away from rafts.
To understand tyrosine kinase signaling mechanisms, we undertook a large-scale study of phosphorylated proteins (phosphoproteomics) in neuroblastoma cell lines. We developed new methods to analyze these data with help from collaborators in the fields of pattern recognition, computational biology and bioinformatics, including Gary Bader (University of Toronto), Paul Shannon (Fred Hutchison Cancer Research Institute) and Wan-Jui Lee and Laurens van der Maaten (Delft University of Technology). Our recent paper (Palacios-Moreno, et al., 2015) was highlighted in Science Daily, Science Newsline Biology, EurekaAlert, A-Z News, MedicalNewsToday, and even the Missoulian. The model is that transient networks of multiprotein complexes, whose assembly is governed by interactions between phosphorylated proteins and phospho-specific protein binding domains, convey information that changes cell fate. These complexes assemble at distinct intracellular locations, and contain different components, in response to activation of different receptor tyrosine kinases. A surprising finding was that more than half of the known RTKs in the human genome were detected in neuroblastoma cell lines, and in most cases several RTKs appear to be active in the same cell line. In several cell lines there are multiple RTKs in endosomes. We also detected the SRC-family kinases, FYN and LYN in endosomes as well as lipid rafts. We hypothesize that the dynamic localization of SRC-family kinases in endosomes and lipid rafts plays a role in distinguishing responses to different RTKs.
Foltz L., Palacios-Moreno, J., Mayfield, M., Kinch, S, Dillon, J.1, Syrenne, J., Levy, T., and Grimes, M. PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation. Molecular Biology of the Cell, in press, 2020. https://doi.org/10.1091/mbc.E20-02-0135
Grimes, M., Hall, B., Foltz, L., Levy, T., Rikova, K., Gaiser, J., Cook, W., Smirnova, E., Wheeler, T., Clark, N. R., Lachmann, A., Zhang, B., Hornbeck, P., Ma’ayan, A., and Comb, M. Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks. Sci. Signal. 11, eaaq1087, 2018
Fernandez, N.L., Gundersen, G.W., Rahman, A., Grimes M.L, Rikova, K., Hornbeck, P., and Ma’ayan, A., Clustergrammer, a web-based heatmap visualization and analysis tool for high-dimensional biological data. Sci Data. 4, 170151, 2017. doi: 10.1038/sdata.2017.151
Palacios-Moreno, J., Foltz, L., Guo, A., Stokes, M. P., Kuehn, E. D., George, L., Comb, M., and Grimes, M. L. Neuroblastoma Tyrosine Kinase Signaling Networks Involve FYN and LYN in Endosomes and Lipid Rafts. PLoS Comp Biol 11, 2015. e1004130–e1004133.
Shannon P, Grimes ML, Kutlu B, Bot JJ, Galas DJ. RCytoscape: Tools for Exploratory Network Analysis. BMC Bioinformatics: 14:217, 2013. doi:10.1186/1471-2105-14-217
Xin X, Gfeller D, Cheng J, Tonikian R, Sun L, et al. SH3 interactome conserves general function over specific form. Mol Syst Biol 9: 652-669, 2013. doi:10.1038/msb.2013.9.
Grimes, M.L., Lee, W.-J., van der Maarten, L., Shannon, P. Wrangling phosphoproteomic data to elucidate cancer signaling pathways.PLoS ONE 8: e52884. doi:10.1371/journal.pone.0052884.t003.
Pryor S., McCaffrey G., Young L.R., Grimes M.L. NGF Causes TrkA to Specifically Attract Microtubules to Lipid Rafts. PLoS ONE 7(4):e35163, 2012. doi:10.1371/journal.pone.0035163
Agnihothram, S. S., B. Dancho, K. W. Grant, M. L. Grimes, D. S. Lyles, and J. H. Nunberg. 2009. Assembly of arenavirus envelopeglycoprotein GPC in detergent-soluble membrane microdomains. J Virol. 83:9890-9900.
McCaffrey, G., Welker, J.,Scott, J., van der Salm, L., and Grimes, M. L. High-resolution fractionation of signaling endosomescontaining different receptors. Traffic 10, 938-950, 2009.
Lin, D.C., Quevedo, C., Brewer, N.E., Testa, J., Grimes, M.L., Miller, F.D., and Kaplan, D.R. (2006). APPL1 associates with TrkA andGIPC1, and is required for NGF-mediated signal transduction. Mol Cell Biol 26, 8928-8941.
MacCormick, M. Moderscheim, T., van der Salm, L.W.M., Moore, A., Clements, S., McCaffrey, G., and Grimes, M.L. Distinct signallingparticles containing Erk/Mek and B-Raf in PC12 cells. Biochemical J 387:155-164, 2005.
Weible, M.W., Ozsarac, N., Grimes, M.L., and Hendry, I.A. Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components. J Neurosci Res 750:771-781, 2004.
Grimes, M.L., and Miettinen, H. Receptor tyrosine kinase and G-protein coupled receptor signalling and sorting within endosomes. JNeurochem, 84: 905-918, 2003.
Francois, F. Godinho, M, Dragunow, M., and Grimes, M.L. A population of PC12 cells that is initiating apoptosis can be rescued by nerve growth factor, Mol Cell Neurosci, 18:347-362, 2001.
Francois F, Godinho, MJ, and Grimes M. L. Creb is cleaved by caspases in neural cell apoptosis. FEBS Lett, 486: 281-284, 2000.
Blythe, T. J., Grimes, M. L. and Kitson, K. E.. "The role of retinoid metabolism by alcohol and aldehyde dehydrogenases in differentiation of cultured neuronal cells." Adv Exp Med Biol 463: 199-204, 1999.
Francois, F, and Grimes, M. L. Phosphorylation-dependent Akt cleavage in neural cell in vitro reconstitution of apoptosis. J. Neurochem.73: 1773-1776, 1999.
Grimes, M. L., Beattie, E., and Mobley, W. C. A signaling organelle containing the nerve growth factor-activated receptor tyrosinekinase, TrkA. Proc. Nat.Acad. Sci. USA 94: 9909-14, 1997.
Beattie, E. C., Zhou, J., Grimes, M. L., Bunnett, N. W., Howe, C. L., and Mobley, W. C. A signaling endosome hypothesis to explainNGF actions: potential implications for neurodegeneration. Cold Spring Harb. Symp. Quant. Biol. 61: 389-406, 1996.
Grimes, M. L., Zhou, J., Beattie, E., Yuen, E.C., Hall, D.E., Valletta, J.S., Topp, K.S., LaVail, J. H., Bunnett, N.W., and Mobley, W.C.Endocytosis of activated TrkA: Evidence that NGF induces formation of Signalling Endosomes. J. Neurosci. 16:7950-7964, 1996.
Zhou J, Valetta JS, Grimes ML, and Mobley WC. Regulation of TrkA expression in PC12 cells after NGF exposure. J.Neurochem. 65:1146-1156, 1995.
Grimes M, Zhou J, Li Y, Holtzman D and Mobley WC. Neurotrophin signaling in the nervous system. Seminars in TheNeurosciences 5:239-247, 1993.
Longo FM, Holtzman DM, Grimes M, and Mobley WC: Nerve Growth Factor: Actions in the Peripheral and Central Nervous System. In: Neurotrophic Factors. Loughlin S, Fallon J (eds.) Academic Press, New York, pp. 209-256. 1993.
Grimes M and Kelly RB. Sorting of chromogranin B into immature secretory granules in pheochromocytoma, PC12 cells. In: Proteases and Protease Inhibitors in Alzheimer?s Disease Pathogenesis. Banner CDB and Nixon RA (eds.) Ann. NY Acad.Sci. 674:38-52, 1992.
Grimes M and Kelly RB. Intermediates in the constitutive and regulated secretory pathways released in vitro from semi-intact cells. J. Cell Biol. 117: 539-550, 1992.
Iacangelo A, Grimes M, and Eiden LE. The bovine chromogranin A gene: Structural basis for hormone regulation and generation of biologically active peptides. Molec. Endocrin. 5: 1651-1660, 1991.
Lloyd RV, Iacangelo A, Eiden LE, Cano M, Jin L and Grimes M. Chromogranin A and B messenger ribonucleic acids in pituitary and other normal and neoplastic human endocrine tissues. Lab. Invest. 60:548-56, 1989.
Grimes M, Iacangelo A, Eiden LE, Godfrey B and Herbert E. Chromogranin A: the primary structure deduced from cDNA clones reveals the presence of pairs of basic amino acids. Ann. NY Acad. Sci. 493:351-78, 1987.
Fricker LD, Liston D, Grimes M and Herbert E. Specificity of Prohormone Processing: The Promise of Molecular Biology. In: Molecular Neurobiology: Recombinant DNA Approaches. Heinemann S and Patrick J. (eds.) Current Topics in Neurobiology Series, New York: Plenum Press, 1987.
Iacangelo A, Affolter HU, Eiden LE, Herbert E and Grimes M. Bovine chromogranin A sequence and distribution of its messenger RNA in endocrine tissues. Nature 323:82-6, 1986.
Nickoloff BJ, Grimes M, Wohlfeil E and Hudson RA. Affinity-dependent cross-linking to neurotoxin sites of the acetylcholine receptor mediated by catechol oxidation. Biochemistry 24:999-1007, 1985.
Nickoloff BJ, Grimes M, Kelly R and Hudson RA. Affinity directed reactions of 3-trimethylaminomethyl catechol with the acetylcholine receptor from Torpedo californica. Biochem. Biophys. Res. Comm. 107:1265-72, 1982.
Specialized Research Interests
Interacting Kinase networks in Neuroblastoma.
Neuroscience Research Interests
My long interest in neurotrophic factor signaling endosomes led to acquisition of phosphoproteomic data on neuroblastoma endosomes and cell lines, which led to new systems biology and computational approaches, which analysis then led my group to a new hypothesis that signaling endosomes play a role in neuronal differentiation by modulating the activity of SRC-family kinases.
A synergy resulted from development of data analysis methods for phosphoproteomics: the clustering methods are useful for analyzing biology education data. Relationships established through participation in the National Academies Summer Institutes Leadership Summit this year led to a new collaboration with leaders in biology education research. Diversity in student attitude, aptitude, background, and response to different teaching methods is widely recognized, yet most education research relies on measurement of trends in the group as a whole, where wide variation in the population often occludes trends in subgroups of students. To understand student learning and response to active learning techniques for different populations of students, there is a clear need to track individual students? progress and analyze data using data-driven clustering methods. We hope that looking at student data in new ways will lead to modification of teaching techniques more accurately tailored to different types of students with different study habits and learning styles, so that future students will be able to choose from a variety of resources that best meet their needs.
1986 - 1987
Postdoctoral Fellow (Advisor: Tom Stevens)
Chemistry Department, University of Oregon, Eugene, OR
1987 - 1991
Postdoctoral Fellow (Advisor: Regis B. Kelly)
Department of Biochemistry and Biophysics, University of California, San Francisco, CA
1991 - 1992
Postdoctoral Fellow (Advisor: William C. Mobley)
Department of Neurology, University of California, San Francisco, CA
1992 - 1994
Assistant Research Cell Biologist
Department of Neurology, University of California, San Francisco, CA
1994 - 2001
Massey University, Palmerston North, New Zealand
2001 - 2001
I worked at Massey University, Palmerston North, New Zealand from 1994 to 2001.
University of Montana Center for Structural and Functional Neuroscience
University of Montana Center for Biomolecular Structure and Dynamics
University of Washington School of Medicine, Department of Physiology & Biophysics