University of Pittsburgh Department of Cell Biology
  • Research

    Research in my lab focuses on the molecular mechanisms regulating the cell polarity. Specifically, epithelial cells develop apical-basal polarity by partitioning the cell surface into distinct apical and basolateral domains through polarized formation of cell junctions. Establishing and maintaining apical-basal polarity is crucial for the function and structure of epithelia, while disruption of such polarity often accompanies the malignant transformation or stress-induced damage of epithelial cells.

    To date a dozen of so-called "polarity proteins" have been identified for their conserved and essential roles in regulating the cell polarity in both vertebrates and invertebrates. A key feature of these polarity proteins is that they must localize to specific apical or basolateral membrane domains to regulate cell polarity, a process generally assumed to be achieved by physical interactions with other polarity proteins or cytoskeleton etc. However, we recently discovered that polarity protein Lgl is targeted to plasma membrane through direct binding between its positively charged polybasic domain and the negative charged inositol phospholipids PIP2 and PI4P on the plasma membrane. Using both Drosophila and cultured mammalian cells as model systems, we are investigating how direct interactions between polarity proteins and plasma membrane lipids may act as a crucial molecular mechanism regulating the subcellular localizations and functions of polarity proteins. The ongoing projects focus on:

    1) Mechanisms regulating the polarized membrane targeting of polarity proteins: Direct binding between Lgl and plasma membrane would localize Lgl to both apical and basolateral membrane domain, rather than exclusively to the basolateral domains. Thus, additional molecular mechanisms must function to fine tune the membrane targeting of polarity proteins. For instance, we are investigating how Lgl membrane targeting is spatially regulated through phosphorylation of Lgl by polarity protein complex aPKC/Par-6.

    2) Role of phospholipids in regulating cell polarity: our discovery that hypoxia acutely and reversibly inhibits Lgl plasma membrane targeting through depleting membrane phospholipids suggests that phospholipid turn-over dynamics and homeostasis play significant role to conserve cell polarity and promote cell survival under cellular stress such as hypoxia/ischemia. 

    3) Plasma membrane targeting of polarity proteins in tumorigenesis:  many polarity proteins, such as Lgl, also function as tumor suppressors. Loss of Lgl membrane targeting is a hallmark in both Drosophila and human tumor cells. We are investigating the mechanism contribute to loss of membrane targeting of polarity proteins and progressive disruption of cell polarity during tumorigenesis.

        To carry out the above projects, we have developed genomic engineering tools that allow efficient generation of knock-in alleles of Drosophila genes. We have also developed comprehensive imaging tools for visualizing the dynamic subcellular localizations of polarity proteins under various physiological conditions including hypoxia.
  • 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. 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;
    3. 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;
    4. 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;
    5. 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;
    6. 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;
    7. 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]
    8. 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]
    9. 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]
    10. 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]
    11. 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.
    12. 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]
    13. 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.
    14. 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]
    15. 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.
    16. 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]
    17. 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]
    18. 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]
    19. 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]
    20. 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]
    21. 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]
    22. 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.
    23. 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]
    24. 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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