University of Pittsburgh Department of Cell Biology

  • Research

    The long term goal of our lab is to elucidate the molecular and cellular mechanisms regulating the cell polarity under normal and diseases conditions (e.g. cancer and ischemia), using Drosophila, cultured cells and animal models.

    A core set of a dozen or so “polarity proteins” play essential and conserved functions in regulating cell polarity in many different cell types. A fundamental process for establishing and maintaining cell polarity is the polarization of polarity proteins to mutually exclusive plasma membrane (PM)/cortical domains. Our current research focuses on how electrostatic interaction between plasma membrane (PM) and polarity proteins acts as a fundamental mechanism for establishing and maintaining cell polarity. We have identified multiple polarity proteins, including Lgl, aPKC and Dlg, as “polybasic polarity proteins” that contain previously unrecognized polybasic domains capable of electrostatically binding PM-enriched phospholipids such as PI4P and PIP2. Our research uncovered diverse mechanisms such as phosphorylation and allosteric conformation changes that control the biological functions and the mutually exclusive PM localizations of polarity protein complexes through regulating their electrostatic PM targeting.



    In addition, we discovered that electrostatic PM targeting of polybasic polarity proteins is highly susceptible to energetic stresses triggered by hypoxia, ATP inhibition and ischemia, which result in the acute and reversible depletion of PM PI4P and PIP2. Challenged by such dramatic energetic stress events, cells demonstrated remarkable resilience in the post-stress recovery of PM PI4P and PIP2, as well as the flawless PM retargeting of polybasic polarity proteins. Mechanisms underlying such cellular resilience presently remain unknown and is an active research topic in the lab.

  • Publications

    1. Lu J, Dong W, Hammond GR, Hong Y. Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2.. Elife. 2022 Jun 9;11():. pii: e79582. doi: 10.7554/eLife.79582. PubMed PMID: 35678383;
    2. Lu J, Dong W, Tao Y, Hong Y. Electrostatic plasma membrane targeting contributes to Dlg function in cell polarity and tumorigenesis.. Development. 2021 Apr 1;148(7):. doi: 10.1242/dev.196956. PubMed PMID: 33688074;
    3. Dong W, Lu J, Zhang X, Wu Y, Lettieri K, Hammond GR, Hong Y. A polybasic domain in aPKC mediates Par6-dependent control of membrane targeting and kinase activity.. J Cell Biol. 2020 Jul 6;219(7):. pii: e201903031. doi: 10.1083/jcb.201903031. PubMed PMID: 32580209;
    4. Hong Y. aPKC: the Kinase that Phosphorylates Cell Polarity.. F1000Res. 2018;7():. pii: F1000 Faculty Rev-903. doi: 10.12688/f1000research.14427.1. PubMed PMID: 29983916;
    5. Cao H, Xu R, Shi Q, Zhang D, Huang J, Hong Y. FERM domain phosphorylation and endogenous 3\'UTR are not essential for regulating the function and subcellular localization of polarity protein Crumbs.. J Genet Genomics. 2017 Aug 20;44(8):409-412. doi: 10.1016/j.jgg.2017.08.002. PubMed PMID: 28844685;
    6. Hammond GR, Hong Y. Phosphoinositides and Membrane Targeting in Cell Polarity.. Cold Spring Harb Perspect Biol. 2017 Mar 6;():. pii: a027938. doi: 10.1101/cshperspect.a027938. PubMed PMID: 28264819;
    7. Chen YJ, Huang J, Huang L, Austin E, Hong Y. Phosphorylation potential of <i>Drosophila</i> E-Cadherin intracellular domain is essential for development and adherens junction biosynthetic dynamics regulation.. Development. 2017 Apr 1;144(7):1242-1248. doi: 10.1242/dev.141598. PubMed PMID: 28219947;
    8. Shao X, Liu Y, Yu Q, Ding Z, Qian W, Zhang L, Zhang J, Jiang N, Gui L, Xu Z, Hong Y, Ma Y, Wei Y, Liu X, Jiang C, Zhu M, Li H, Li H. Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b.. Cell Res. 2016 May;26(5):593-612. doi: 10.1038/cr.2016.34. PubMed PMID: 26987402;
    9. Dong W, Zhang X, Liu W, Chen YJ, Huang J, Austin E, Celotto AM, Jiang WZ, Palladino MJ, Jiang Y, Hammond GR, Hong Y. A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. J Cell Biol. 2015 Oct 19. pii: jcb.201503067. [Epub ahead of print] [link]
    10. Yuva-Aydemir Y, Xu XL, Aydemir O, Gascon E, Sayin S, Zhou W, Hong Y, Gao FB. Downregulation of the Host Gene jigr1 by miR-92 Is Essential for Neuroblast Self-Renewal in Drosophila. PLoS Genet. 2015 May 22;11(5):e1005264. doi: 10.1371/journal.pgen.1005264. eCollection 2015 May. [link]
    11. Liu K, Lin Q, Wei Y, He R, Shao X, Ding Z, Zhang J, Zhu M, Weinstein LS, Hong Y, Li H, Li H. Gαs regulates asymmetric cell division of cortical progenitors by controlling Numb mediated Notch signaling suppression. Neurosci Lett. 2015 Jun 15;597:97-103. doi: 10.1016/j.neulet.2015.04.034. Epub 2015 Apr 24. [link]
    12. Haltom AR, Lee TV, Harvey BM, Leonardi J, Chen YJ, Hong Y, Haltiwanger RS, Jafar-Nejad H. The protein O-glucosyltransferase Rumi modifies eyes shut to promote rhabdomere separation in Drosophila. PLoS Genet. 2014 Nov 20;10(11):e1004795. doi: 10.1371/journal.pgen.1004795. eCollection 2014 Nov. [link]
    13. Zhou W, Hong Y. Drosophila Patj plays a supporting role in apical-basal polarity but is essential for viability. Development. 2012 Aug;139(16):2891-6. doi: 10.1242/dev.083162. Epub 2012 Jul 12. PubMed PMID: 22791898; PubMed Central PMCID: PMC3403101.
    14. Zhou W, Huang J, Watson AM, Hong Y. W::Neo: a novel dual-selection marker for high efficiency gene targeting in Drosophila. PLoS One. 2012;7(2):e31997. doi: 10.1371/journal.pone.0031997. Epub 2012 Feb 13. [link]
    15. Huang J, Huang L, Chen YJ, Austin E, Devor CE, Roegiers F, Hong Y. Differential regulation of adherens junction dynamics during apical-basal polarization. J Cell Sci. 2011 Dec 1;124(Pt 23):4001-13. doi: 10.1242/jcs.086694. Epub 2011 Dec 8. PubMed PMID: 22159415; PubMed Central PMCID: PMC3244983.
    16. Huang J, Ghosh P, Hatfull GF, Hong Y. Successive and targeted DNA integrations in the Drosophila genome by Bxb1 and phiC31 integrases. Genetics. 2011 Sep;189(1):391-5. doi: 10.1534/genetics.111.129247. Epub 2011 Jun 6. [link]
    17. Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Pan D. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7. doi: 10.1073/pnas.1004279107. Epub 2010 May 24. PubMed PMID: 20498073; PubMed Central PMCID: PMC2890787.
    18. Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010 Apr 13;20(7):582-90. doi: 10.1016/j.cub.2010.03.019. Epub 2010 Apr 1. [link]
    19. Huang J, Zhou W, Dong W, Hong Y. Targeted engineering of the Drosophila genome. Fly (Austin). 2009 Oct-Dec;3(4):274-7. Epub 2009 Oct 1. [link]
    20. Huang J, Zhou W, Dong W, Watson AM, Hong Y. From the Cover: Directed, efficient, and versatile modifications of the Drosophila genome by genomic engineering. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8284-9. doi: 10.1073/pnas.0900641106. Epub 2009 May 8. [link]
    21. Huang J, Zhou W, Watson AM, Jan YN, Hong Y. Efficient ends-out gene targeting in Drosophila. Genetics. 2008 Sep;180(1):703-7. doi: 10.1534/genetics.108.090563. Epub 2008 Aug 30. [link]
    22. Hristova M, Birse D, Hong Y, Ambros V. The Caenorhabditis elegans heterochronic regulator LIN-14 is a novel transcription factor that controls the developmental timing of transcription from the insulin/insulin-like growth factor gene ins-33 by direct DNA binding. Mol Cell Biol. 2005 Dec;25(24):11059-72. [link]
    23. Hong Y, Ackerman L, Jan LY, Jan YN. Distinct roles of Bazooka and Stardust in the specification of Drosophila photoreceptor membrane architecture. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12712-7. Epub 2003 Oct 20. [link]
    24. Hong Y, Stronach B, Perrimon N, Jan LY, Jan YN. Drosophila Stardust interacts with Crumbs to control polarity of epithelia but not neuroblasts. Nature. 2001 Dec 6;414(6864):634-8. PubMed PMID: 11740559.
    25. Hong Y, Lee RC, Ambros V. Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in Caenorhabditis elegans. Mol Cell Biol. 2000 Mar;20(6):2285-95. [link]
    26. Hong Y, Roy R, Ambros V. Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans. Development. 1998 Sep;125(18):3585-97. [link]

     

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