Skip navigation

The Meyer Lab Home Page

Research statement

The Meyer laboratory seeks to understand how human cells sense hormones, growth factors 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 the key signaling components and measuring when and where signaling occurs as we watch cells decide to move forward or enter the cell cycle. We have been intrigued by the near universal importance of locally acting Ca2+ and phosphoinositide lipid second messenger signals, Rho and Ras family small GTPases and protein kinases in controlling these decision processes. Our projects are focused on understanding the general principles of how signal transduction systems work which often requires the development of new experimental and analysis tools involving fluorescent microscopy, small molecule and light perturbations, systematic siRNA screens, bioinformatics, genomics and quantitative modeling of signaling pathways.


February 2015: Gautam's paper is out in Cell Reports !

Functional links between genes can be predicted using phylogenetic profiling, by correlating the appearance and loss of homologs in subsets of species. However, effective genome-wide phylogenetic profiling has been hindered by the large fraction of human genes related to each other through historical duplication events. Here, we overcame this challenge by automatically profiling over 30,000 groups of homologous human genes (orthogroups) representing the entire protein-coding genome across 177 eukaryotic species (hOP profiles). By generating a full pairwise orthogroup phylogenetic co-occurrence matrix, we derive unbiased genome-wide predictions of functional modules (hOP modules). Our approach predicts functions for hundreds of poorly characterized genes. The results suggest evolutionary constraints that lead components of protein complexes and metabolic pathways to co-evolve while genes in signaling and transcriptional networks do not. As a proof of principle, we validated two subsets of candidates experimentally for their predicted link to the actin-nucleating WASH complex and cilia/basal body function. Check out the web server accompanying the paper

November 2014: A new postdoc joins the lab !

Damien Garbett joined the Meyer lab as a postdoctoral fellow. Welcome aboard Damien !

August 2014: Sean and Sabrina are opening their own labs !

Contratulations to Sean who got a position in UC Davis and to Sabrina who is opening her lab in UC Boulder. Good luck in your new ways! we will miss you.

November 2013: Kyuho's paper is out in Nature Methods !

Protein concentrations are often regulated by dynamic changes in translation rates. Nevertheless, it has been challenging to directly monitor changes in translation in living cells. We have developed a reporter system to measure real-time changes of translation rates in human or mouse individual cells by conjugating translation regulatory motifs to sequences encoding a nuclear targeted fluorescent protein and a controllable destabilization domain. Application of the method showed that individual cells undergo marked fluctuations in the translation rate of mRNAs whose 5′ terminal oligopyrimidine (5′ TOP) motif regulates the synthesis of ribosomal proteins. Furthermore, we show that small reductions in amino acid levels signal through different mTOR-dependent pathways to control TOP mRNA translation, whereas larger reductions in amino acid levels control translation through eIF2A. Our study demonstrates that dynamic measurements of single-cell activities of translation regulatory motifs can be used to identify and investigate fundamental principles of translation.

October 2013: Jia-Yun's paper is out in Molecular Cell !

Mammalian cells have a remarkable capacity to compensate for heterozygous gene loss or extra gene copies. One exception is Down syndrome (DS), where a third copy of chromosome 21 mediates neurogenesis defects and lowers the frequency of solid tumors. Here we combine live-cell imaging and single-cell analysis to show that increased dosage of chromosome 21-localized Dyrk1a steeply increases G1 cell cycle duration through direct phosphorylation and degradation of cyclin D1 (CycD1). DS-derived fibroblasts showed analogous cell cycle changes that were reversed by Dyrk1a inhibition. Furthermore, reducing Dyrk1a activity increased CycD1 expression to force a bifurcation, with one subpopulation of cells accelerating proliferation and the other arresting proliferation by costabilizing CycD1 and the CDK inhibitor p21. Thus, dosage of Dyrk1a repositions cells within a p21-CycD1 signaling map, directing each cell to either proliferate or to follow two distinct cell cycle exit pathways characterized by high or low CycD1 and p21 levels.

September 2013: Sabrina's paper is out in Cell !

Tissue homeostasis in metazoans is regulated by transitions of cells between quiescence and proliferation. The hallmark of proliferating populations is progression through the cell cycle, which is driven by cyclin-dependent kinase (CDK) activity. Here, we introduce a live-cell sensor for CDK2 activity and unexpectedly found that proliferating cells bifurcate into two populations as they exit mitosis. Many cells immediately commit to the next cell cycle by building up CDK2 activity from an intermediate level, while other cells lack CDK2 activity and enter a transient state of quiescence. This bifurcation is directly controlled by the CDK inhibitor p21 and is regulated by mitogens during a restriction window at the end of the previous cell cycle. Thus, cells decide at the end of mitosis to either start the next cell cycle by immediately building up CDK2 activity or to enter a transient G0-like state by suppressing CDK2 activity.

September 2013: Welcome Chad and Felix !

Chad liu and Felix Horns and rotating in our lab. Welcome guys !

Sep 2013: Three accepted papers in the last two weeks ! Congrats Sabrina, Jia-Yun and Kyuho

More details soon

Congrats Feng-Chiao, Jia-Yun and Milos

Feng Chiao, Jia-Yun and Milos are moving on. We will miss you guys ! Good luck on your new journeys

July 2013: Sam and Seth's paper is out in Science signaling !

Assigning molecular functions and revealing dynamic connections between large numbers of partially characterized proteins in regulatory networks are challenges in systems biology. We showed that functions of signaling proteins can be discovered with a differential equations model of the underlying signaling process to extract specific molecular parameter values from single-cell, time-course measurements. By analyzing the effects of 250 small interfering RNAs on Ca2+ signals in single cells over time, we identified parameters that were specifically altered in the Ca2+ regulatory system. Analysis of the screen confirmed known functions of the Ca2+ sensors STIM1 (stromal interaction molecule 1) and calmodulin and of Ca2+ channels and pumps localized in the endoplasmic reticulum (ER) or plasma membrane. Furthermore, we showed that the Alzheimer’s disease–linked protein presenilin-2 and the channel protein ORAI2 prevented overload of ER Ca2+ and that feedback from Ca2+ to phosphatidylinositol 4-kinase and PLC{delta} (phospholipase C{delta}) may regulate the abundance of the plasma membrane lipid PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to control Ca2+ extrusion. Thus, functions of signaling proteins and dynamic regulatory connections can be identified by extracting molecular parameter values from single-cell, time-course data.

Nov 2012: Roy's paper is out in Nature Cell Biology !

The actin cortex both facilitates and hinders the exocytosis of secretory granules. How cells consolidate these two opposing roles was not well understood. Here we show that antigen activation of mast cells induces oscillations in Ca(2+) and PtdIns(4,5)P(2) lipid levels that in turn drive cyclic recruitment of N-WASP and cortical actin level oscillations. Experimental and computational analysis argues that vesicle fusion correlates with the observed actin and Ca(2+) level oscillations. A vesicle secretion cycle starts with the capture of vesicles by actin when cortical F-actin levels are high, followed by vesicle passage through the cortex when F-actin levels are low, and vesicle fusion with the plasma membrane when Ca(2+) levels subsequently increase. Thus, cells employ oscillating levels of Ca(2+), PtdIns(4,5)P(2) and cortical F-actin to increase secretion efficiency, explaining how the actin cortex can function as a carrier as well as barrier for vesicle secretion.

Aug 2012: Milos paper is out in Nature Cell Biology !

Many of the more than 20 mammalian proteins with N-BAR domains1, 2 control cell architecture3 and endocytosis4, 5 by associating with curved sections of the plasma membrane6. It is not well understood whether N-BAR proteins are recruited directly by processes that mechanically curve the plasma membrane or indirectly by plasma-membrane-associated adaptor proteins that recruit proteins with N-BAR domains that then induce membrane curvature. Here, we show that externally induced inward deformation of the plasma membrane by cone-shaped nanostructures (nanocones) and internally induced inward deformation by contracting actin cables both trigger recruitment of isolated N-BAR domains to the curved plasma membrane. Markedly, live-cell imaging in adherent cells showed selective recruitment of full-length N-BAR proteins and isolated N-BAR domains to plasma membrane sub-regions above nanocone stripes. Electron microscopy confirmed that N-BAR domains are recruited to local membrane sites curved by nanocones. We further showed that N-BAR domains are periodically recruited to curved plasma membrane sites during local lamellipodia retraction in the front of migrating cells. Recruitment required myosin-II-generated force applied to plasma-membrane-connected actin cables. Together, our results show that N-BAR domains can be directly recruited to the plasma membrane by external push or internal pull forces that locally curve the plasma membrane

Jan 2012: Jia-Yun's paper is out in Molecular Cell !

A two-dimensional ERK-AKT code decides between proliferation and differentiation ► Single-cell signal variation creates two cell fates in an identical cell population ► Different growth factor inputs are integrated at the level of ERK and AKT ► Rasa2 enhances proliferation over differentiation in a population of PC12 cells.

Last modified Thursday, 12-Feb-2015 15:07:19 PST