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Primary Faculty
Peter N. Devreotes, Ph.D.
The Isaac Morris and Lucille Elizabeth Hay Professor
Director, Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe St., 114 WBSB
Baltimore, MD 21205
 
   
Telephone: 410-955-3225 (Office)
  410-955-4699 (Lab)
Fax: 410-614-9461
Email: pnd@jhmi.edu
Website: http://www.hopkinsmedicine.org/cellbio/devreotes/
Assistant: Pam Antol, 410-502-6810, pjantol@jhmi.edu
Other Affiliations: • Secondary Appointment in Biological Chemistry
  • Center for Cell Dynamics
 

 

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.

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 a complete 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.

 

Select Publications

Iglesias, P.A. and Devreotes, P.N. 2012. Biased excitable networks: how cells direct motion in response to gradients. Curr. Opin. Cell Biol., 757:451-468.

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 Iglesias, P.A. and Devreotes, P.N. 2012 Biased excitable networks: how cells direct motion in response to gradients. Curr. Opin. Cell Biol., 757:451-468.

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.

Kamimura, Y., and Devreotes, P.N.  2010.  Phosphoinositide-dependent protein kinase (PDK) activity regulates phosphatidylinositol 3,4,5-trisphosphate-dependent and -independent protein kinase B activation and chemotaxis.  J Biol Chem 285(11):7938-7946.

Tang, L., Franca-Koh, J., Xiong, Y., Chen, M-Y., Long, Y., Bickford, R.M., Knecht, D.A., Iglesias, P.A., and Devreotes, P.N.  2008. Tsunami, the Dictyostelium homolog of the Fused kinase is required for polarization and chemotaxis.  Genes Dev. 22:2278-2290.

Kamimura, Y., Xiong, Y., Iglesias, P.A., Hoeler, O., Bolourani, P. and Devreotes, P.N.  2008. PIP(3)-Independent activation of TorC2 and PKB at the cell's leading edge mediates chemotaxis.  Curr. Bio. 18:1034-43.

Chen, L., Iijima, M., Tang, M., Landree, M.A., Huang, Y.E., Xiong, Y., Iglesias, P.A., and Devreotes, P.N.  2007.  PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis.  Dev. Cell 12(4):603-614.

Janetopoulos, C., Ma, L., Iglesias, P.A., and Devreotes, P.N.  2004. Chemoattractant-induced temporal and spatial PI(3,4,5)P3 accumulation is controlled by a local excitation, global inhibition mechanism. PNAS 101(24):8951-8956.

Janetopoulos, C. and Deverotes, P.N. 2003.  Eukaryotic Chemotaxis:  Distinctions between directional sensing and polarization.   J. Biol. Chem. 278, 20445-20448.

Iijima, M. and Devreotes, P. N. 2002. Tumor suppressor PTEN mediates sensing of chemoattractant gradients.  Cell 109, 599-610 (Cover).

Ueda, M., Sako, Y., Tanaka, T., Devreotes, P., and Yanagida, T.  2001. Single molecule analysis of chemotactic signaling in Dictyostelium cells.  Science, 294(5543), 864-7.

Janetopoulos, C., Jin, T. and Devreotes, P. 2001. Receptor-Mediated Activation of Heterotrimeric G-proteins in Living Cells. Science 291, 2408-2411.

Parent, C. and Devreotes, P. 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, M.-Y., Long, Y. and Devreotes, P.N. 1997. A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the twelve transmembrane domain adenylyl cyclase in Dictyostelium. Genes and Development 11, 3218-3231.

Xiao, Z., Zhang, N., Murphy, D.B. and Devreotes, P.N. 1997. Dynamic distribution of chemoattractant receptors in living cells during chemotaxis and persistent stimulation. J. Cell Biol. 139, 365-374.

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, K.J. and Devreotes, P.N. 1981. Cyclic AMP waves in Dictyostelium discoideum: A demonstration by isotope dilution fluorography. Science 212, 443-446. (COVER)

 

 

 

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