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Chemotaxis plays a key role in immune response, wound healing, angiogenesis, and embryogenesis as well as mediating cancer metastasis. Research in Dictyostelium discoideum has shown that chemoattractants are sensed by GPCRs and rapidly trigger a complex network of signaling pathways. Our strategy is to use the genetics of Dictyostelium to discover mechanisms by which cells sense chemical gradients and to apply this information to other eukaryotic cells such as human neutrophils and epithelial cells. We found that cell motility depends on spontaneous activation of the signal transduction network and that directional cues bias the activation. Cell motility results from coupling of signal transduction and cytoskeletal networks. The signal transduction network, comprised of multiple pathways that include Ras GTPases, PI(3)K and Rac GTPases is excitable, exhibiting wave propagation, refractoriness and maximal response to suprathreshold stimuli, even in the absence of a funtional cytoskeleton. We have been able to exploit the excitable nature of the signal transduction network to force cells into different modes of migration. When the threshold of the excitable network is lowered in amoeboid cells, they first transition to a “fan” mode resembling the movement of a keratocyte. They then begin to display slow global oscillations, and finally they assume an extremely flattened “pancake” mode. Thus, the set point of the excitable signal transduction network controls the type of protrusion cells make and how they move. We are now working on the idea that chemoattractants and other cues such as mechanical forces are integrated to modulate the setpoint differently at the front and rear of migrating cells. .
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 mode. Nat Cell Biol March 27. Doi: 10.1038/ncb3495. [Epub ahead of print]. PMID: 28346441
Artemenko Y, Axiotakis L Jr., Borleis J, Iglesias PA, Devreotes PN. 2016. Chemical and mechanical stimuli act on common signal transduction and cytoskeletal networks. Proc Natl Acad Sci U S A. 2016 Nov 22; 113(47):E7500-E7509. PMCID: PMC5127353
Swaney K.F., Borleis J., Iglesias P.A., and Devreotes, P.N. 2015. Novel protein Callipygian defines the back of migrating cells. Proc Natl Acad Sci U S A. Jun 30. Pii:201509098 [Epub ahead of print]. PMID: 26130809.
Cai,H., Katoh-Kurasawa, M., Muramoto, T., Santhanam, B., Long, Y., Li L., Ueda, M., Iglesias P.A., Shaulsky, G., and Devreotes, P.N. 2014. Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer. Science. Mar 21;343(6177):1249531. Doi: 10.1126/science.1249531. PMCID: PMC4061987.
Huang, C.,Tang, M., Shi, C.,Iglesias, P., and Devreotes, P.N. 2013. An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. Nat Cell Biol. Nov;15(11):1307-16. PMCID: PMC3838899.
Tang, M., Iijima, M., and Devreotes, P.N. 2011. Generation of cells that ignore the effects of PIP3 on cytoskeleton. Cell Cycle, 10:2817-2818. PMCID: PMC3218594.
Tang, M., Iijima, M., Kamimura, Y., Chen, L., Long, Y., and Devreotes, P.N. 2011. Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN. Mol. Biol. Cell. 22:437-447. PMCID: PMC3038642.
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. PMCID: PMC4364543. .
Jiao Z, Cai H, Long Y, Sirka OK, Padmanaban V, Ewald AJ and Devreotes PN. 2020. Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects. Proc Natl Acad Sci U S A. 2020 Feb 25; 117(8): 4158-4168. doi: 10.1073/pnas.1917938117. PMC7049144.
Zhan H, Bhattacharya S, Cai H, Iglesias PA, Huang C-H and Devreotes PN. 2020. An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells. Dev Cell. 2020 Sep 14;54(5):608-623.e5. doi: 10.1016/j.devcel.2020.08.001. PMC7505206 (available on 2021-09-14).
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. PMCID: PMC2951443.
Rahdar, M., Inoue, T., Meyer T., Zhang, J., Vazquez, F., Devreotes, P.N. 2008. A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. PNAS 106:480-485. PMCID: PMC2626728.
Janetopoulos, C., Borleis, J., Vazquez, F., Iijima, M., and Devreotes, P.N. 2005. Temporal and spatial regulation of phosphoinositide signaling mediates cytokinesis. Dev. Cell 8:467-477.
Iijima M, Devreotes P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell. 2002 May 31;109(5):599-610. doi: 10.1016/s0092-8674(02)00745-6. PMID: 12062103.
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. 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).