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Primary Faculty  
Douglas Robinson, Ph.D.
Professor
Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe St., 100 Physiology
Baltimore, MD 21205
Telephone: 410-502-2850 (Office)
410-502-4905 (Lab)
Fax: 410-955-4129
Email: dnr@jhmi.edu
Website: http://www.hopkinsmedicine.org/cellbio/ robinson/ index.html

Affiliations:

Center for Cell Dynamics
BCMB Graduate Program
Pharmacology and Molecular Sciences
Chemical and Biomolecular Engineering

 

 

 

 

 

 

 

 
Research Topic:  Cytokinesis and Cell Shape Control

Cell division is essential for growth and replenishment of tissues and organs and to achieve this renewal, the human body has nearly a billion cell division events underway at every moment in time.  However, no cellular process is 100% efficient, and cell division failure is deleterious, leading to tumorigenesis.  We apply a range of genetic, molecular, chemical, biochemical, biophysical, and engineering methods to discover new factors involved in cytokinesis and to learn how they contribute to the process.  By combining these approaches, we are developing a sophisticated understanding of how myosin-II motor proteins and actin crosslinking proteins govern cell shape changes.  We are also identifying the pathways that regulate these factors, controlling cellular contractility.

Recently, we discovered a novel mechanosensory system that allows dividing cells to sense shape perturbations so that the cells can correct the disturbance and complete cytokinesis normally. Mechanosensing is fundamental to a wide variety of cellular processes critical to healthy and pathological states. Tumor cells can grow in the absence of surface attachment, a feature that classically defines cellular transformation, indicating that changes in mechanotransduction are an important part of cancer progression. Bone remodeling, blood pressure regulation, and hearing are all examples of normal processes that depend on mechanosensing.  Yet, the cellular and molecular mechanisms of mechanosensing are not well understood in any system.  Using molecular genetics in combination with micromechanical approaches, we are discerning the contributions from molecular motors, microtubule network, actin-associated proteins, and signaling proteins to mechanosensing during cell division.

 

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 lead 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. We have discerned the mechanics that drive this process, and identified how the cell senses external forces (mechanosensing) and transmits them to changes in the chemical signaling pathways that guide cytokinesis. While we continue to study how these processes direct cytokinesis, we are also learning how these same principles apply to diseases such as cancer. For example, we have identified how mechanical cues guide aberrant behaviors of breast cancer cells. In this case, we found that cancer and non-cancer cells can compete with each other, and due to their unique mechanical properties, the winner cell (typically the cancer cell) can engulf and kill the loser cell (often the healthy cell). In another project, we are exploring how cellular growth control pathways and cell mechanics are interlinked. In one example, we have found that a key regulatory pathway, which guides liver formation and leads to liver cancer if the pathway becomes uncontrolled, also controls the hepatocyte mechanical properties. We are also studying how various molecular lesions that drive pancreatic cancer progression control cell mechanics. Our work based on Dictyostelium cytokinesis paints a particular picture (a hypothesis) of what happens to pancreatic ductal epithelial cells as they acquire the various molecular changes that lead to metastatic disease. We are trying to test this hypothesis. Finally, we have found that many of 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 cell mechanical defects could contribute to some types of human infertility and/or birth defects.

 

Selected Publications

Kabacoff C, Srivastava V, Robinson DN. A Summer Academic Research Experience for Disadvantaged Youth. CBE Life Sci. Educ. 2013; In press.

Robinson DN, Iglesias PA. Bringing the physical sciences into your cell biology research. Mol. Biol. Cell 2012; 23(21): 4167-4170.

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.

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.

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.

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.

 

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Updated: 8/20/13

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