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Personal Summary

Press on TV: , , 

UM: /news/2023/04/041823canc.php, /news/2024/04/041024cart.php

Other press: , , , , , 

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

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, and found a novel method for generating craniofacial organoids from neural crest cells. Organoids are a simplified, miniature version of an organ that mimic the architecture and gene expression of the organ, and they are a good way to study human tissues in ways that are not possible using tissue from human beings. Through extensive analysis of biological markers at the RNA and protein level, and machine-learning pattern-recognition techniques, we sought to understand the cell signaling pathways involved when cells differentiate into cartilage from stem cells. We uncovered several cell signaling pathways that are activated when stem cells become elastic cartilage, which makes up human ears. Growing cartilage in the laboratory also could lead to effective treatments to repair craniofacial cartilage damage due to injuries and address a critical unmet need for new methods to regenerate human cartilage for the 230,000 children born annually in the U.S. with craniofacial defects.

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 (; ). 

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 was highlighted in Science Daily, Science Newsline Biology, , , , and even the . 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

McTee, M., Casper, C., Deeble, B., Grimes, M., Henning, M., Jourdonnais, C., and Ramsey, P. (2025). Evaluating the precision and velocity of factory vs. handloaded lead‐free ammunition. Wildlife Society Bulletin. 10.1002/wsb.1570.

Avabhrath, N., Foltz, L., and Grimes, M. (2024). Protocol for generating human craniofacial cartilage organoids from stem-cell-derived neural crest cells. STAR Protoc 6, 103532. 10.1016/j.xpro.2024.103532. 

Foltz, L., Avabhrath, N., Lanchy, J.-M., Levy, T., Possemato, A., Ariss, M., Peterson, B., and Grimes, M. (2024). Craniofacial chondrogenesis in organoids from human stem cell-derived neural crest cells. iScience 27. .

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. 

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. 

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. Sci. Signal. 11, eaaq1087, 2018

Fernandez, N.L., Gundersen, G.W., Rahman, A., Grimes M.L, Rikova, K., Hornbeck, P., and Ma’ayan, A., , 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. . PLoS Comp Biol 11, 2015. e1004130–e1004133.

Shannon P, Grimes ML, Kutlu B, Bot JJ, Galas DJ. . 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. .PLoS ONE 8: e52884. doi:10.1371/journal.pone.0052884.t003. 

Pryor S., McCaffrey G., Young L.R., Grimes M.L.  . 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. . J Virol. 83:9890-9900.

McCaffrey, G., Welker, J.,Scott, J., van der Salm, L., and Grimes, M. L. . 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). . 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.  . Biochemical J 387:155-164, 2005.

Weible, M.W., Ozsarac, N., Grimes, M.L., and Hendry, I.A.  . J Neurosci Res 750:771-781, 2004.

Grimes, M.L., and Miettinen, H. . JNeurochem, 84: 905-918, 2003.

Francois, F. Godinho, M, Dragunow, M., and Grimes, M.L.  , Mol Cell Neurosci, 18:347-362, 2001.

Francois F, Godinho, MJ, and Grimes M. L. .  FEBS Lett, 486: 281-284, 2000.

Blythe, T. J., Grimes, M. L. and Kitson, K. E.. "." Adv Exp Med Biol 463: 199-204, 1999.

Francois, F, and Grimes, M. L. . J. Neurochem.73: 1773-1776, 1999.

Grimes, M. L., Beattie, E., and Mobley, W. C. .  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. . 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.. J. Neurosci. 16:7950-7964, 1996. 

Zhou J, Valetta JS, Grimes ML, and Mobley WC.  . J.Neurochem.  65:1146-1156, 1995.

Grimes M, Zhou J, Li Y, Holtzman D and Mobley WC.  .  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:  .  Loughlin S, Fallon J (eds.)  Academic Press, New York, pp. 209-256. 1993. 

Grimes M and Kelly RB.  .  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. .  J. Cell Biol. 117: 539-550, 1992.

Iacangelo A, Grimes M, and Eiden LE.  .  Molec. Endocrin. 5: 1651-1660, 1991.

Lloyd RV, Iacangelo A, Eiden LE, Cano M, Jin L and Grimes M.  .  Lab. Invest. 60:548-56, 1989.

Grimes M, Iacangelo A, Eiden LE, Godfrey B and Herbert E.  .  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: .  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.  .  Nature 323:82-6, 1986.

Nickoloff BJ,  Grimes M,  Wohlfeil E and  Hudson RA.  .  Biochemistry 24:999-1007, 1985.

Nickoloff BJ,  Grimes M,  Kelly R and Hudson RA.  .  Biochem. Biophys. Res. Comm. 107:1265-72, 1982.

Affiliations

����ֱ�� Center for Translational Medicien

����ֱ�� Center for Structural and Functional Neuroscience 

����ֱ�� 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.