The Meyer lab seeks to understand how human cells sense hormones, growth factors, cell contacts and stress and how they integrate and transduce these signals to make decisions to polarize, move or divide. We investigate these cellular regulatory systems by identifying key signaling components and measure when and where signaling occurs by using live-cell microscopy approaches to watch cells signal and decide to move forward or enter the cell cycle. Our projects are focused on understanding the general principles of how mammalian signal transduction systems work which requires the development and application of new experimental and analysis tools including advanced fluorescent microscopy techniques, small molecule and light perturbations, systematic genomic and targeted screens, RNAseq technologies, bioinformatics, organoids and other in vitro and in vivo models, and quantitative modeling of signaling pathways.
Understanding the control of mammalian cell-cycle entry using single-cell microscopy approaches
Ongoing control of cell proliferation is needed to maintain tissue function throughout life. Regulation of both cell-cycle entry and exit is important as most adult mammals have subsets of stem, progenitor and differentiated cells that can switch between proliferation and quiescence. The goal of our work is to understand the underlying signaling system how normal mammalian cells as well as cancer cells control cell-cycle entry and exit decision processes using cultured cell models, organoids and in vivo single-cell analysis. This is an interesting problem in cell signaling as cells integrate tens of external hormones, growth factors, cell contacts as well as many internal stress and metabolic signals to ultimately make a single decision. We recently made a number of advances to understand this cell-cycle entry signaling system and have now critical techniques in place to provide definite answers to major open questions. Specifically, our laboratory has been developing a series of approaches based on live single-cell reporter measurements of cyclin D-CDK4/6, cyclin E/A-CDK2 and APC/CCDH1 activities, rapid perturbation strategies as well as methods based on fixed single-cell analysis. We can use these methods to automatically measure multiple activities and expression levels and localization of signaling proteins and mRNAs in the same cell.
See the following publications for more about this work:
- Cappell SD, Mark KG, Garbett D, Pack LR, Rape M, Meyer T. 2018. EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle. Nature. 558, 313-317.
- Daigh LH, Liu C, Chung M, Cimprich KA, Meyer T. 2018. Stochastic endogenous replication stress causes ATR-triggered fluctuations in CDK2 activity that dynamically adjust the global DNA synthesis rate. Cell Systems. 7, 17-27.
- Saldivar JC, Hamperl S, Bocek MJ, Chung M, Bass TE, Cisneros-Soberanis F, Samejima K, Xie L, Paulson JR, Earnshaw WC, Cortez D, Meyer T, Cimprich KA. 2018. An intrinsic S/G2 checkpoint enforced by ATR. Science. 361, 806-810.
- Yang HW, Chung M, Kudo T, Meyer T. 2017. Competing memories of mitogen and p53 signalling control cell-cycle entry. Nature. 549, 404-408.
- Cappell SD, Chung M, Jaimovich A, Spencer SL, Meyer T. 2016. Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry. Cell. 166, 167-80.
- Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T. 2013. The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit. Cell. 155, 369-83.
- Chen JY, Lin JR, Tsai FC, Meyer T. 2013. Dosage of Dyrk1a Shifts Cells within a p21-Cyclin D1 Signaling Map to Control the Decision to Enter the Cell Cycle. Mol Cell. 52, 87-100.
Understanding cell contact inhibition of cell division and movement by regulating growth signal transduction at the plasma membrane.
One of the open questions in the control of cell division and movement is the mechanism how cells sense contact with other cells and then transduce these signals to control cell-cycle entry and polarized migration. We are particularly excited about recent findings of the role of polarization of signaling activities that result from polarized distribution of cortical actin, membrane curvature, ER-plasma membrane junctions, receptors, actin bundling proteins and other structural and signaling components. In future work, we seek for example to answer the question how the same signaling pathways are often used to polarize cells and also to trigger proliferation. A key part of these projects are the use of micropatterned surfaces, the development of 2 and 3D models as well as in vivo studies using mammalian tissue sections to investigate cell movement and proliferation in an in vitro and more physiological context.
See the following publications for more about this work:
- Gan L, Seki A, Shen K, Iyer H, Han K, Hayer A, Wollman R, Ge X, Lin J, Dey G, Talbot WS, Meyer T. 2019. The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity. Nature Cell Biology. (in press, May 2019)
- Hayer A, Shao L, Chung M, Jouber LM, Yang HW, Tsai FC, Bisaria A, Betzig E, Meyer T. 2016. Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol. 18, 1311-1323.
- Yang HW, Collins SR, Meyer T. 2016. Locally excitable Cdc42 signals steer cells during chemotaxis. Nat Cell Biol. 18, 191-201.
- Winans AM, Collins SR, Meyer T. 2016. Waves of actin and microtubule polymerization drive microtubule-based transport and neurite growth before single axon formation. Elife. 5, e12387.
- Tsai FC, Seki A, Yang HW, Hayer A, Carrasco S, Malmersjö S, Meyer T. 2014. A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration. Nat Cell Biol. 16, 133-44.
- Han K, Jaimovich A, Dey G, Ruggero D, Meyuhas O, Sonenberg N, Meyer T. 2014. Parallel measurement of dynamic changes in translation rates in single cells. Nature Methods. 11, 86-93.
- Habib SJ, Chen BC, Tsai FC, Anastassiadis K, Meyer T, Betzig E, Nusse R. 2013. A localized Wnt signal orients asymmetric stem cell division in vitro. Science. 339, 1445-8.
- Wollman R, Meyer T. 2012. Coordinated oscillations in cortical actin and Ca(2+) correlate with cycles of vesicle secretion. Nat Cell Biol. 14, 1261-9.
- Galic M, Jeong S, Tsai FC, Joubert LM, Wu YI, Hahn KM, Cui Y, Meyer T. 2012. External push and internal pull forces recruit curvature-sensing N-BAR domain proteins to the plasma membrane. Nat Cell Biol. 14, 874-81.