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Peter N. Devreotes, Ph.D.

Peter N. Devreotes, Ph.D.

Academic Titles: 
Isaac Morris and Lucille Elizabeth Hay Professor
Position Title: 
Director, Department of Cell Biology
Appointments/Affiliations: 

Secondary appointments in Biological Chemistry and Center for Cell Dynamics
BCMB Graduate Program

410-955-3225 (Office)
410-955-4699 (Lab)
410-614-9461 (Fax)

Johns Hopkins University School of Medicine
725 N. Wolfe St., 114 WBSB
Baltimore, MD 21205

Research Topic:  Genetic analysis of chemotaxis in eukaryotic cells

Many cells have an internal “compass” that allows them to detect and move along extracellular chemical gradients in a process referred to as chemotaxis or directed cell migration. In embryogenesis, chemotaxis is used repeatedly to rearrange cells, for instance, during primordial germ cell migration, organ formation, and wiring of the nervous system. In the adult, chemotaxis mediates normal trafficking of immune cells and is critical for inflammation. It also participates in wound healing, in maintenance of tissue architecture, and allows stem cells to target to and persist in their niches.

Chemotaxis bias depends on a network composed of multiple signaling pathways. Several years ago, we discovered that chemoattractants activate PI3Ks producing an accumulation of PIP3 at the leading edge of amoebae. We now know that this mechanism is conserved in neutrophils and many other types of eukaryotic cells. Unregulated production of PIP3, as occurs in cells lacking the tumor suppressor PTEN, causes many ectopic projections and impairs the directional response of migrating cells. Thus, localized PIP3 production is an important conserved mechanism mediating chemotactic bias. However, additional pathways act in parallel or redundantly with PIP3.

In our search for parallel pathways, we have found that TorC2 is activated at the leading edge of the cell and causes the localized activation of PKBs and phosphorylation of PKB substrates. The absence of these phosphorylation events in cells lacking PiaA leads to a defect in chemotaxis. This pathway acts in parallel with PIP3 to mediate the chemotactic response. It has recently been found that the TorC2 mechanism is conserved in chemotaxing neutrophils. Most recently, using TIRF, we have found that signaling events propagate in waves along the basal surface of the cell.  We are investigating how these spontaneous signaling waves coordinate the activity of the cytoskeleton to make cellular protrusions.

Our long term goal is acomplete description of the network controlling chemotactic behavior. We are analyzing combinations of deficiencies to understand interactions among network components and carrying out additional genetic screens to identify new pathways involved in chemotaxis. A comprehensive understanding of this fascinating process should lead to control of pathological conditions such as inflammation and cancer metastasis.
 

 

Research Interest: 
Genetic analysis of chemotaxis in eukaryotic cells
Research Associates and Staff:
Name Position title Email Phone
Michelle Clark Senior Research Service Analyst mclark@jhmi.edu 410-614-3602
Randy Huffman Administrator randy@jhu.edu 410-614-4207
Brigitte Walsh Assistant to the Director bwalsh12@jhmi.edu 410-502-6810
Lab Members:
Namesort descending Classification Email Phone
Budri Sharif Student budri@jhmi.edu
Huiwang (David) Zhan Student huiwangzhan@jhmi.edu 410-955-4699
Jane Borleis Research Specialist jborleis@jhmi.edu 410-955-4699
Marc Edwards, Ph.D. Postdoctoral Fellow medwar33@jhu.edu 410-955-4699
Wei Qian Research Technologist wqian1@jhmi.edu 410-955-3225
Xiaoguang Li Student xli82@jhmi.edu 410-955-4699
Yu Long Research Specialist yulong@jhmi.edu 410-955-4699
Yuchuan Miao Student ymiao1@jhmi.edu 410-955-4699
Zhihua Jiao, Ph.D. Postdoctoral Fellow zjiao3@jhu.edu 410-955-4699
Research

Biological oscillations are universally found in nature and are critical at many levels of cellular organization. In the model organism we study, the social amoeba Dictyostelium discoideum, starvation-triggered cell-cell aggregation and developmental morphogenesis are orchestrated by periodic extracellular cAMP waves, which provide both gradients for chemotactic migration and signals for development. Repeated occupancy of the G protein–coupled cAMP receptors promotes optimal developmental gene expression, whereas continuous stimulation suppresses the program.

Selected Publications:
Lampert TJ, Kamprad N, Edwards M, Borleis J, Watson AJ, Tarantola M, Devreotes PN.  2017. Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity. Proc Natl Acad Sci USA Aug 28. Pii: 201616600. Doi: 10.1073/pnas.1616600114. [Epub ahead of print]. PMID: 28847951
Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X, Devreotes P, Wolberger C, Amzel M, Gabelli SB, Cole PA.  2017. A Tunable Brake for HECT Ubiquitin Ligases. Molecular Cell 66 (3): 345-357. PMID: 28475870. DOI: 10.1016/j.molcel.2017.03.020
Miao Y, Bhattacharya S, Edwards M, Cai H, Inoue T, Iglesias P, Devreotes PN. 2017.  Altering the threshold of an excitable signal transduction network changes cell migratory modes.  Nat Cell Biol 19:329-340.
Artemenko Y, Axiotakis L Jr., Borleis J, Iglesias PA, Deveotes PN. 2016. Chemical and mechanical stimuli act on common signal transduction and cytoskeletal networks. Proc Natl Acad Sci USA. Nov. 22; 113(47):E7500-E7509. PMCID: PMC5127353 [ link ]
Swaney K.F., Borleis J., Iglesias P.A., and Devreotes, P.N. 2015.  Novel protein Callipygian defines the back of migrating cells. PNAS 2015 Jun 30. pii:201509098. [Epub ahead of print]
Tang M, Wang M, Shi C, Iglesias PA, Devreotes PN, and Huang CH  (2014).  Evolutionarily conserved coupling of adaptive and excitable networks mediates eukaryotic chemotaxis. Nat Commun. Oct 27;5:5175. PMCID: PMC4211273 [Available on 2015/4/27)]
Cai H, Katoh-Kurasawa M, Muramoto T, Santhanam B, Long Y, Li L, Ueda M, Iglesias PA, Shaulsky G, and Devreotes PN. Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer. Science. 2014 Mar 21;343(6177):1249531. doi: 10.1126/science.1249531.
Huang, C.,Tang, M., Shi, C., Iglesias, P., and Devreotes, P.N. An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. Nat Cell Biol. 2013 Nov;15(11):1307-16.
Shi, C., Huang, C., Devreotes, P.N., and Iglesias, P.  2013. Interaction of motility, directional sensing, and polarity modules recreates the behaviors of chemotaxing cells. PLOS Computational Biol. 2013 Jul;9(7):e1003122. 
Cai, H., Das, S., Kamimura, Y., Comer, F.I., Parent, D.A., and Devreotes, P.N.  2010  Ras-mediated activation and inactivation of the TorC2-PKB pathway are critical for chemotaxis.  J. Cell Biol., 190:233-245. PMCID: PMC2930282
Swaney, K.F., Huang, C.H., Devreotes, P.N. 2010. Eukaryotic Chemotaxis: A network of signaling pathways controls motility, directional sensing, and polarity. Annu Rev Biophys 278:20445-20448.
Xiong, Y., Huang, C-H, Iglesias, P.A., and Devreotes, P.N. 2010. Cells navigate with a local-excitation, global-inhibition-biased excitable network. PNAS, 107:17079-17086.
Janetopoulos C, Ma L, Devreotes PN, Iglesias PA. Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is spatially amplified and adapts, independent of the actin cytoskeleton. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8951-6. PMC428453
Iijima, M. and Devreotes, P. N. 2002. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109, 599-610 (Cover).
Janetopoulos, C., Jin, T. and Devreotes, P.N. 2001. Receptor mediated activation of heterotrimeric G-proteins in living cells. Science, 291, 2408-2411.
Parent, C. and Devreotes, P.N. 1999. A Cell's Sense of Direction. Science, 284, 765-770.
Parent, C., Blacklock, B., Froelich, W., Murphy, D. and Devreotes, P.N. 1998. G protein signaling events are activated at the leading edge of chemotactic cells. Cell, 95, 81-91.
Chen MY, Long Y, Devreotes PN. A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the 12 transmembrane domain adenylyl cyclase in Dictyostelium. Genes Dev. 1997 Dec 1;11(23):3218-31. PMC316743
Xiao Z, Zhang N, Murphy DB, Devreotes PN. Dynamic distribution of chemoattractant receptors in living cells during chemotaxis and persistent stimulation. J Cell Biol. 1997 Oct 20;139(2):365-74. PMC2139806
Insall R, Kuspa A, Lilly PJ, Shaulsky G, Levin LR, Loomis WF, Devreotes P. CRAC, a cytosolic protein containing a pleckstrin homology domain, is required for receptor and G protein-mediated activation of adenylyl cyclase in Dictyostelium. J Cell Biol. 1994 Sep;126(6):1537-45. PMC2290948
Lilly P, Wu L, Welker DL, Devreotes PN. A G-protein beta-subunit is essential for Dictyostelium development. Genes Dev. 1993 Jun;7(6):986-95. PMID: 8099335.
Pitt, G.S., Milona, N., Borleis, J., Lin, K.C., Reed, R.R. and Devreotes, P.N. 1992. Structurally distinct and stage-specific adenylyl cyclase genes play different roles in Dictyosteilum development. Cell 69, 305-315.
Klein, P.S., Sun, T.L., Saxe, C.L. III, Kimmel, A.R., Johnson, R.L. and Devreotes, P.N.  1988.  A chemoattractant receptor controls development in Dictyostelium discoideum. Science 241, 1467-1472.
Tomchik KJ, Devreotes PN. Adenosine 3',5'-monophosphate waves in Dictyostelium discoideum: a demonstration by isotope dilution--fluorography. Science. 1981 Apr 24;212(4493):443-6. (Cover Article). PMID: 6259734
Devreotes PN, Steck TL. Cyclic 3',5' AMP relay in Dictyostelium discoideum. II. Requirements for the initiation and termination of the response. J Cell Biol. 1979 Feb;80(2):300-9. PMC2110342