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Douglas Robinson, Ph.D.

Douglas Robinson, Ph.D.

Academic Titles: 
Professor
Position Title: 
Principal Investigator
410-502-2850 (Office)
410-502-4905 (Lab)
410-955-4129 (Fax)

Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe Street, 100 Physiology
Baltimore, MD 21205

Research Summary

Multi-cellular living organisms grow from single cells into multicellular, complex systems composed of highly diverse cell-types organized into tissues, which in turn form organs and organ systems. To organize and maintain this complex architecture, the organism must undergo constant renewal through cell proliferation and elimination of unwanted cells. This process of tissue development and homeostasis requires chemical and mechanical information to be sensed by the cells within the tissues, and in turn, interpreted to guide their decision making: to divide, migrate, constrict, or die. Failure in these processes leads to diverse diseases, such as hypertension, degeneration, and cancer. We have been studying cytokinesis (cell division) as a model cell behavior that incorporates internally generated signals with external mechanical cues to drive healthy cell shape change.

Using a simple model organism Dictyostelium discoideum, we have discerned the mechanics that drive cytokinesis, and identified how the cell senses external forces (mechanosensing) and transmits them to changes in the chemical signaling pathways that guide cytokinesis. Working with computational biologist Pablo Iglesias (JHU Electrical and Computer Engineering), we have reached the point where we have a highly quantitative understanding of cytokinesis and cellular mechanosensing, which is based on measured parameters and has predictive power. We continue to pursue important fundamental questions using this model organism and cell process.

While we study how these processes direct cytokinesis, we are also learning how these same principles apply to diseases such as cancer, lung and motor neuron diseases. To accomplish such broad goals, we collaborate closely with a several basic and clinical scientists. For example, with Mike Overholtzer (Memorial Sloan Kettering), we determined how mechanical cues guide aberrant behaviors in breast cancer. Here, we found that cancer and non-cancer cells compete with each other, and due to their unique mechanical properties, the cancer cell can engulf and kill the non-cancer cell. Working with Bob Anders (JHU Pathology), we are examining how changes in cell mechanics correlate with pancreatic ductal adenocarcinoma cancer (PDAC) progression. In this context, key molecular changes associated with disease progression are also known to regulate central elements of the cell's contractile machinery. We are finding that many of the mechanosensory proteins undergo dramatic changes in expression as a normal pancreatic ductal epithelial cell progresses to metastatic disease. With Ramana Sidhaye (JHU Pulmonology), we are exploring the acute changes to cellular architecture that occur in the lung epithelia in response to insults such as cigarette smoke, which can ultimately lead to diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. Fascinatingly, many of the same principles apply to degenerative motor neuron disease, and we have found a way to apply our fundamental discoveries here too by working with Charlotte Sumner and Tom Lloyd (JHU Neurology). Finally, in collaboration with Janice Evans (Bloomberg School of Public Health), we found that these same principles apply to the development of a mammalian egg where disruption of the cell mechanics machinery causes defects in the formation of a healthy egg; such defects could be the cause of some types of human infertility and/or birth defects.

We are also leveraging our sophisticated understanding of cytokinesis, cell mechanics, and cellular mechanosensing to identify and develop small molecule modulators (i.e. possible future drugs) of cell mechanics. Such tools will be invaluable for dissecting tissue mechanics during normal development, tissue homeostasis, and pathological situations such as tumor formation and metastasis. To identify and develop small molecule modulators of cell mechanics, we draw upon the fact that cytokinesis in the simple amoeba Dictyostelium discoideum is exquisitely sensitive to changes in cell mechanics and that perturbation of these mechanics leads to an easily measurable phenotype, which is the formation of multinucleated cells. Towards this goal, we developed an automated image analysis platform called CIMPAQ for high-throughput drug screening for such modulators. In initial experiments, we identified a novel compound, carbamate-7, which shifts one of the major cell mechanics proteins myosin II into the cell skin (cell cortex) where it increases cortical tension and elasticity. We are testing the active component of this compound in several of the disease systems described above and already have found that the compound can correct the aberrant mechanics of metastatic cells. With Bob Anders, we will soon initiate animal studies to test the ability of the compound to alter the trajectory of metastatic disease.

Overall, our program seeks to determine how cells and tissues integrate chemical and mechanical information flow for normal tissue growth and homeostasis with the ultimate goal of being able to guide these processes with small molecules for therapeutic purposes. Starting from a simple model system, we are able to uncover and dissect fundamental principles of cell biology that would be next to impossible to discover in more complex situations. Then, by knowing what to look for, we find the same principles underlie various diseases, which we are then working to correct with small molecules (potential future drugs).

 

Research Interest: 
Molecular Mechanisms of Cell Shape Control from Model Systems to Disease States.
Research Associates and Staff:
Name Position titlesort descending Email Phone
Alexandra Surcel, Ph.D. Research Associate asurcel1@jhmi.edu 410-502-4905
Lab Members:
Name Classification Email Phone
Shantel Angstadt Student sangsta1@jhmi.edu 410-502-4905
Kathleen DiNapoli Student kdinapo1@jhmi.edu 410-502-4905
Cathryn Kabacoff Research Technologist ckabaco1@jhmi.edu 410-502-4905
Corrine Kliment, M.D., Ph.D. Postdoctoral Fellow kliment.corrine@gmail.com 410-502-4905
Priyanka Kothari Student pkothar6@jhmi.edu 410-502-4905
Yinan Liu Student ylin234@jhmi.edu 410-502-4905
Jennifer Nguyen Student jnguye27@jhmi.edu 410-502-4905
Eleana Parajón Student eparajo1@jhu.edu 410-502-4905
Eric Schiffhauer Student eschiff1@jhmi.edu 410-502-4905
Dustin Thomas, Ph.D. Postdoctoral Fellow dthom20@jhmi.edu 410-502-2850
Brian Woolums Student bwoolum1@jhu.edu 410-502-3249
Selected Publications:
Schiffhauer E, Robinson DN. 2017. Mechanochemical signaling directs cell shape change. Biophys. J. 112: 207-214. (Featured article)
Kothari P, Schiffhauer E, Robinson DN. Cytokinesis from nanometers to micrometers and microseconds to minutes. 2017. Methods Cell Biol. 137:307-322.
Ibo M, Srivastava V, Robinson DN, Gagnon Z. Cell blebbing in confined microfluidic environments. PLoS One 2016; 11(10): e0163866.
Bai H, Zhu Q, Surcel A, Luo T, Ren Y, Guan B, Liu Y, Wu N, Joseph NE, Wang T-L, Zhang N, Pan D, Alpini G, Robinson DN, Anders RA. Yes-Associated Protein impacts adherens junction assembly through regulating actin cytoskeleton organization. Am. J. Physiol. – Gastrointest. Liver Phys. 2016; In press.
Srivastava V, Iglesias PA, Robinson DN*. 2016. Cytokinesis: Robust cell shape regulation. Semin. Cell Dev. Biol. 2016; 53:39-44.
Schiffhauer ES, Luo T, Mohan K, Srivastava V, Qian X, Griffis E, Iglesias PA, Robinson DN*. Mechanoaccumulative elements of the mammalian actin cytoskeleton. Curr. Biol. 2016; 26: 1473-1479.
Mackenzie ACL, Kyle DD, McGinnis LA, Lee HJ, Aidana N, Robinson DN, Evans JP. Cortical mechanics and myosin-II abnormalities associated with post-ovulatory aging:  Implications for functional defects in aged eggs. Mol. Hum. Reprod. 2016; 22(6):397-409.
Christianson MS, Gerolstein AL, Lee HJ, Monseur BC, Robinson DN, Evans JP. Effects of inhibition of Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) on sperm incorporation and cortical tension in mouse eggs. Mol. Reprod. Dev. 2016; 83(3): 188-189.
Kim JH, Ren Y, Ng WP, Li S, Son S, Kee Y-S, Zhang S, Zhang G, Fletcher DA, Robinson DN, Chen EH. Mechanical tension drives cell membrane fusion. Dev. Cell 2015; 561-573. 
Srivastava V, Robinson DN. Mechanical stress and network structure drive protein dynamics during cytokinesis. Curr. Biol. 2015; 25(5): 663-670. 
Surcel A, Ng W-P, West-Foyle H, Zhu Q, Ren Y, Avery L, Krenc AK, Meyers D, Rock RS, Anders RA, Freel Meyers C, Robinson DN*. Pharmacological activation of myosin II paralogs to correct cell mechanics defects. Proc. Natl. Acad. Sci. USA 2015; 112(5): 1428-1433. 
Ren Y, West-Foyle H, Surcel A, Miller C, Robinson DN. Genetic suppression of a phosphomimic myosin II identifies system-level factors promoting myosin II cleavage furrow accumulation. Mol. Biol. Cell. 2014; 25: 4150-4165.
Sun Q, Luo T, Ren Y, Shirasawa S, Sasazuki T, Cibas ES, Hodgson L, Robinson DN, Overholtzer M. Competition between human cells by entosis. Cell Res. 2014; 24: 1299-1310.
Luo T, Mohan K, Iglesias PA, Robinson DN. Molecular mechanisms of cellular mechanosensing. Nat. Mater. 2013; 12: 1064-1071.
Kee YS, Ren Y, Dorfman D, Iijima M, Firtel RA, Iglesias PA, Robinson DN. A mechanosensory system governs myosin II accumulation in dividing cells. Mol. Biol. Cell 2012; 23(8): 1510-1523.
Poirier CC, Ng WP, Robinson DN, Iglesias PA. Deconvolution of the cellular force-generating subsystems that govern cytokinesis furrow ingression. PLoS Comp. Biol. 2012; 8(4): e1002467. 
Dickinson D, Robinson DN, Nelson WJ, Weis WI. α-catenin and IQGAP regulate myosin localization to control epithelial tube morphogenesis in Dictyostelium. Dev. Cell 2012; 23: 533-546.
Luo T, Mohan K, Srivastava V, Ren Y, Iglesias PA, Robinson DN. Understanding the cooperative interactions between myosin II and actin crosslinkers mediated by actin filaments during mechanosensation. Biophys. J. 2012; 102(2): 238-247. 
Zhou Q, Kee Y-S, Poirier CC, Jelinek C, Osborne J, Divi S, Surcel A, Tran ME, Eggert US, Müller-Taubenberger A, Iglesias PA, Cotter RJ, Robinson DN. 14-3-3 coordinates microtubules, Rac, and myosin II to control cell mechanics and cytokinesis. Curr. Biol. 2010; 20:1881-1889.
Larson SM, Lee HJ, Hung P-h, Matthews LM, Robinson DN, Evans JP. Cortical mechanics and meiosis II completion in mammalian oocytes are mediated by myosin-II and ezrin-radixin-moesin (ERM) proteins. Mol. Biol. Cell 2010; 21:3182-3192.
Ren Y, Effler JC, Norstrom M, Luo T, Firtel RA, Iglesias PA, Rock, RS, Robinson DN. Mechanosensing through cooperative interactions between myosin-II and the actin crosslinker cortexillin-I. Curr. Biol. 2009; 19(17):1421-1428.
Reichl EM, Ren Y, Morphew MK, Delannoy M, Effler JC, Girard KD, Divi S, Iglesias PA, Kuo SC, Robinson DN.* 2008. Interactions between myosin and actin crosslinkers control cytokinesis contractility dynamics and mechanics. Curr. Biol. 18: 471-480. PMCID: PMC2361134
Effler JC, Kee Y-S, Berk JM, Tran MN, Iglesias PA, Robinson DN.* Mitosis-specific mechanosensing and contractile protein redistribution control cell shape. Curr. Biol. 2006; 16(19):1962-1967. PMCID: PMC2474462
Zhang W., Robinson DN.* Balance of actively generated contractile and resistive forces controls cytokinesis dynamics. Proc. Natl. Acad. Sci. USA 2005; 102(20):7186-7191. PMCID: PMC1129136
Robinson DN*, Spudich JA. Dynacortin, a genetic link between equatorial contractility and global shape control discovered by library complementation of a Dictyostelium cytokinesis mutant. J. Cell Biol. 2000; 150(4):823-838. PMCID: PMC2175282