University of Pittsburgh Department of Cell Biology
  • Research

    The human heart beats upwards of 100,000 times a day, and contractile forces place unique physical and regulatory demands on the protein complexes that join cardiomyocytes together to form a functional heart muscle. Mechanical coupling and chemical communication between cardiomyocytes is accomplished through a specialized adhesive structure called the intercalated disc (ICD). The ICD comprises adherens junctions and desmosomes that connect the actin and intermediate filament cytoskeletons, respectively, to the plasma membrane. ICD formation requires multiple adhesion and cytoskeletal proteins, and mutations in these proteins can cause cardiomyopathies. However, little is known about how these adhesive complexes are assembled or regulated to withstand the forces of cardiomyocyte contraction and maintain tissue integrity.

    A long-term objective of work in the Kwiatkowski lab is to gain a deep mechanistic understanding of cardiomyocyte adhesion and cytoskeletal organization at the ICD. Our approach is to define mechanisms of cell-cell adhesion, and downstream regulation of actin and intermediate filament organization, by the cadherin-catenin adhesion complex, the core of the adherens junction. Our rationale is that understanding the molecular mechanisms of adherens junction adhesion in cardiomyocytes may provide fundamental insight into cardiomyocyte cell-cell adhesion and adherens junction biology. Understanding the molecular mechanisms of cell-cell adhesion in cardiomyocytes will provide the foundation for determining how mutations in ICD proteins cause heart disease and inform the development of new strategies for the treatment of cardiomyopathies.

  • Publications

    1. Raza Q, Choi JY, Li Y, O\'Dowd RM, Watkins SC, Chikina M, Hong Y, Clark NL, Kwiatkowski AV. Evolutionary rate covariation analysis of E-cadherin identifies Raskol as a regulator of cell adhesion and actin dynamics in Drosophila.. PLoS Genet. 2019 Feb;15(2):e1007720. doi: 10.1371/journal.pgen.1007720. PubMed PMID: 30763317;
    2. Wickline ED, Dale IW, Merkel CD, Heier JA, Stolz DB, Kwiatkowski AV. αT-Catenin Is a Constitutive Actin-binding α-Catenin That Directly Couples the Cadherin·Catenin Complex to Actin Filaments.. J Biol Chem. 2016 Jul 22;291(30):15687-99. doi: 10.1074/jbc.M116.735423. PubMed PMID: 27231342;
    3. Hansen SD*, Kwiatkowski AV*, Ouyang C, Liu H, Pokutta S, Volkmann N, Hanein D, Weis WI, Mullins RD, Nelson WJ. Alpha-catenin actin binding domain alters actin filament conformation and regulates binding of nucleation and disassembly factors. Mol Biol Cell. Dec;24(23):3710-20. PMID: 24068324 *Co-first author
    4. Miller PW, Pokutta S, Ghosh A, Almo SC, Weis WI, Nelson WJ, Kwiatkowski AV. Danio rerio αE-catenin is a monomeric F-actin binding protein with distinct properties from Mus musculus αE-catenin. J Biol Chem. 2013 Aug 2;288(31):22324-32. doi: 10.1074/jbc.M113.458406. Epub 2013 Jun 20. PubMed PMID: 23788645; PubMed Central PMCID: PMC3829323.
    5. Kwiatkowski AV*, Maiden SL*, Pokutta S, Choi HJ, Benjamin JM, Lynch AM, Nelson WJ, Weis WI, Hardin J. In vitro and in vivo reconstitution of the cadherin-catenin-actin complex from Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14591-6. doi: 10.1073/pnas.1007349107. Epub 2010 Aug 5. Erratum in: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4264. [link] *Co-first author
    6. Benjamin JM*, Kwiatkowski AV*, Yang C, Korobova F, Pokutta S, Svitkina T, Weis WI, Nelson WJ. AlphaE-catenin regulates actin dynamics independently of cadherin-mediated cell-cell adhesion. J Cell Biol. 2010 Apr 19;189(2):339-52. doi: 10.1083/jcb.200910041. [link] *Co-first author
    7. Kwiatkowski AV, Garner CC, Nelson WJ, Gertler FB. Cell autonomous defects in cortical development revealed by two-color chimera analysis. Mol Cell Neurosci. 2009 May;41(1):44-50. doi: 10.1016/j.mcn.2009.01.008. Epub 2009 Feb 5. [link]
    8. Dent EW, Kwiatkowski AV, Mebane LM, Philippar U, Barzik M, Rubinson DA, Gupton S, Van Veen JE, Furman C, Zhang J, Alberts AS, Mori S, Gertler FB. Filopodia are required for cortical neurite initiation. Nat Cell Biol. 2007 Dec;9(12):1347-59. Epub 2007 Nov 18. [link]
    9. Furman C, Sieminski AL, Kwiatkowski AV, Rubinson DA, Vasile E, Bronson RT, Fässler R, Gertler FB. Ena/VASP is required for endothelial barrier function in vivo. J Cell Biol. 2007 Nov 19;179(4):761-75. Epub 2007 Nov 12. [link]
    10. Kwiatkowski AV*, Rubinson DA*, Dent EW, Edward van Veen J, Leslie JD, Zhang J, Mebane LM, Philippar U, Pinheiro EM, Burds AA, Bronson RT, Mori S, Fässler R, Gertler FB. Ena/VASP Is Required for neuritogenesis in the developing cortex. Neuron. 2007 Nov 8;56(3):441-55. [link] *Co-first author


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