Graduate Student Research Mentors

Neuroscience Graduate Program (NGP) faculty are committed to mentoring students pursuing BS/MS, MS or PhD degrees within their active lab groups that also include postdoctoral fellows, technicians, and undergraduate students. NGP faculty have strong records of funding from NIH, NSF and a variety of private foundations. Their research interests reflect the breadth and depth of the NPG and highlight the many exciting opportunities open to students.

Mark Grimes

Professor, DBS

Contact

Office
Health Sciences 306
Phone
(406) 243-4977
Email
Mark.Grimes@mso.umt.edu
Curriculum Vitae
View/Download CV

Education

B.A. Kalamazoo College, 1978

Ph.D. University of Oregon, 1986

Courses Taught

Biology 260 Cell and Molecular Biology

Biology/Biochemistry 600 Cell Organization and Mechanisms

Biology 160 Principles of Living Systems

Teaching Experience

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.

Research Interests

 

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. We initiated a project to derive neural crest stem cells (NCSCs) from human embryonic stem cells (hESCs) because of an interest in how cells differentiate.  The study of cell signaling mechanisms in cancer is highly relevant to mechanisms that drive cell differentiation. Cancer arises by various mechanisms as cells break out of their normal differentiated state in multicellular organisms, and neuroblastoma begins with an early failure in neural crest differentiation during development. To study cell signaling mechanisms, we have developed computational approaches to analyze large data sets of proteins and protein post-translational modifications. Our techniques employ machine learning to help recognize patterns from statistical relationships in data, and combine that information with protein-protein interactions to visualize data structure as networks at different levels. Recently, we have added another level to these network models of data structure that elucidates interactions among cell signaling pathways. This study has received some interest from the press (https://medicalxpress.com/news/2023-04-ai-lung-cancer-cell-vulnerabilities.html; https://www.khq.com/the_630/360-coverage-university-of-montana-team-uses-ai-to-study-lung-cancer/video_848fe82d-c1bf-53d5-a0da-d12d9bdec912.html). 

We have also used cell biological approaches to study cell signaling and membrane traffic in a study that directly addresses mechanisms of cell differentiation. 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 fractionated neuroblastoma cells to examine the location of signaling proteins in different membranes and organelles and learned that the scaffold protein, PAG1, which was known to control SRC-family kinase (SFK) activity in lipid rafts, was one of the most highly phosphorylated proteins in neuroblastoma endosomes. This led to discovery of a novel cell signaling mechanism that distinguishes receptor tyrosine kinase (RTK) promotion of neuronal differentiation vs. proliferation: PAG1 influences SFK sequestration in multivesicular bodies and is required for differentiation but not proliferation. In addition, we transplanted neuroblastoma cells into developing chick embryos and showed that neuroblastoma cells were multipotent, capable of migrating and differentiating into many cell types expected of normal neural crest cells.

Our paper (Palacios-Moreno, et al., 2015) was highlighted in Science DailyScience Newsline Biology, EurekaAlertA-Z NewsMedicalNewsToday, 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. We hypothesize that the dynamic localization of SRC-family kinases in endosomes and lipid rafts plays a role in distinguishing responses to different RTKs.    

 

 

Publications

Ross, K.E., Zhang, G., Akcora, C., Lin, Y., Fang, B., Koomen, J., Haura, E.B., and Grimes, M. (2023). Network models of protein phosphorylation, acetylation, and ubiquitination connect metabolic and cell signaling pathways in lung cancer. PLoS Comput Biol 19, e1010690. 10.1371/journal.pcbi.1010690. Download PDF

Foltz, L.E., Levy, T., Possemato, A., and Grimes, M.L. (2021). Craniofacial cartilage organoids from human embryonic stem cells via a neural crest cell intermediate. bioRxiv. 10.1101/2021.05.31.446459.

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, 31, 2269-2282, 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 AnalysisBMC Bioinformatics: 14:2172013. 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 microdomainsJ 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 receptorsTraffic 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, 18:347-3622001.

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.

Affiliations

University of Montana Center for Translational Medicien

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  

Professional Experience

 

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

Senior Lecturer

Massey University, Palmerston North, New Zealand

 

2001 - 2001

International Experience

I worked at Massey University, Palmerston North, New Zealand from 1994 to 2001.

Honors / Awards

1979        Graduate Teaching Fellow, Chemistry Department, University of Oregon

1980        NIH Molecular Biology Predoctoral Training Grant GM 07759, Institute of Molecular Biology, University of Oregon 

1986        American Heart Association Research Fellow, American Heart Association, Oregon Affiliate, Inc.

1987     NIH Neurobiology Postdoctoral Training Grant  NS 07067-10,    Department of Physiology, University of California, San Francisco

1988         National Research Service Award  NS 08387-01, National Institute of Neurological and Communicative Disorders and Stroke

1991    Athena Neurosciences Special Fellowship, Athena Neurosciences, South San Francisco, CA

1992    NARSAD Young Investigator Award, National Alliance for Research on Schizophrenia and Depression, Great Neck, NY

2007    National Academies Education Fellow in the Life Sciences, National Academy of Sciences

2011    National Academies Education Mentor in the Life Sciences, National Academy of Sciences

2018-21    Scientific Teaching Host Leader and Mentor, Summer Institutes for Scientific Teaching, National Science Foundation, Howard Hughes Medical Institute, Yale University Center for Scientific Teaching.