All Publications


  • Fluctuation relations for non-Markovian and heterogeneous temperature systems PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS Korkmazhan, E. 2020; 537
  • Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction. eLife Kan, W. n., Enos, M. D., Korkmazhan, E. n., Muennich, S. n., Chen, D. H., Gammons, M. V., Vasishtha, M. n., Bienz, M. n., Dunn, A. R., Skiniotis, G. n., Weis, W. I. 2020; 9

    Abstract

    In Wnt/β-catenin signaling, the transcriptional coactivator β-catenin is regulated by its phosphorylation in a complex that includes the scaffold protein Axin and associated kinases. Wnt binding to its coreceptors activates the cytosolic effector Dishevelled (Dvl), leading to the recruitment of Axin and the inhibition of β-catenin phosphorylation. This process requires interaction of homologous DIX domains present in Dvl and Axin, but is mechanistically undefined. We show that Dvl DIX forms antiparallel, double-stranded oligomers in vitro, and that Dvl in cells forms oligomers typically <10 molecules at endogenous expression levels. Axin DIX (DAX) forms small single-stranded oligomers, but its self-association is stronger than that of DIX. DAX caps the ends of DIX oligomers, such that a DIX oligomer has at most four DAX binding sites. The relative affinities and stoichiometry of the DIX-DAX interaction provide a mechanism for efficient inhibition of β-catenin phosphorylation upon Axin recruitment to the Wnt receptor complex.

    View details for DOI 10.7554/eLife.55015

    View details for PubMedID 32297861

  • Dynamics of translation can determine the spatial organization of membrane-bound proteins and their mRNA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Korkmazhan, E., Teimouri, H., Peterman, N., Levine, E. 2017; 114 (51): 13424–29

    Abstract

    Unlike most macromolecules that are homogeneously distributed in the bacterial cell, mRNAs that encode inner-membrane proteins can be concentrated near the inner membrane. Cotranslational insertion of the nascent peptide into the membrane brings the translating ribosome and the mRNA close to the membrane. This suggests that kinetic properties of translation can determine the spatial organization of these mRNAs and proteins, which can be modulated through posttranscriptional regulation. Here we use a simple stochastic model of translation to characterize the effect of mRNA properties on the dynamics and statistics of its spatial distribution. We show that a combination of the rate of translation initiation, the availability of secretory apparatuses, and the composition of the coding region determines the abundance of mRNAs near the membrane, as well as their residence time. We propose that the spatiotemporal dynamics of mRNAs can give rise to protein clusters on the membrane and determine their size distribution.

    View details for PubMedID 29203677

  • Sub-cellular mRNA localization modulates the regulation of gene expression by small RNAs in bacteria. Physical biology Teimouri, H., Korkmazhan, E., Stavans, J., Levine, E. 2017

    Abstract

    Small non-coding RNAs can exert significant regulatory activity on gene expression in bacteria. In recent years, substantial progress has been made in understanding bacterial gene expression by sRNAs. However, recent findings that demonstrate that families of mRNAs show non-trivial sub-cellular distributions raise the question of how localization may affect the regulatory activity of sRNAs. Here we address this question within a simple mathematical model. We show that the non-uniform spatial distributions of mRNA can alter the threshold-linear response that characterizes sRNAs that act stoichiometrically, and modulate the hierarchy among targets co-regulated by the same sRNA. We also identify conditions where the sub-cellular organization of cofactors in the sRNA pathway can induce spatial heterogeneity on sRNA targets. Our results suggest that under certain conditions, interpretation and modeling of natural and synthetic gene regulatory circuits need to take into account the spatial organization of the transcripts of participating genes.

    View details for DOI 10.1088/1478-3975/aa69ac

    View details for PubMedID 28350301

  • FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature JOURNAL OF CLINICAL INVESTIGATION Sabine, A., Bovay, E., Demir, C. S., Kimura, W., Jaquet, M., Agalarov, Y., Zangger, N., Scallan, J. P., Graber, W., Gulpinar, E., Kwak, B. R., Makinen, T., Martinez-Corral, I., Ortega, S., Delorenzi, M., Kiefer, F., Davis, M. J., Djonov, V., Miura, N., Petrova, T. V. 2015; 125 (10): 3861-3877

    Abstract

    Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

    View details for DOI 10.1172/JCI80454

    View details for Web of Science ID 000362311700017

    View details for PubMedID 26389677

    View details for PubMedCentralID PMC4607114