University of Pittsburgh Department of Cell Biology
  • Research

    Peptide bond hydrolysis is one of the final common events leading to cellular injury and death. Excessive proteolytic activity occurs in virtually all disease states including cancer, atherosclerosis, autoimmunity and infection. To counter the deleterious effects of proteolytic activity, cells express several groups of anti-proteases, of which the serine protease inhibitors (serpins) superfamily is the largest. Serpins evolved over 1000 million years and employ a unique suicide substrate-like inhibitory mechanism to neutralize target proteases. We have characterized a novel subset of serpins that, unlike the canonical circulating serpins such as α1-antitrypsin (SERPINA1), reside predominantly within the cell. The intracellular serpins (serpinsIC) are conserved in all metazoa, lack typical signal peptides and neutralize a diversity of serine and, paradoxically, cysteine proteases. We are using transgenic models in mice and the small nematode, C. elegans, to determine how serpinsIC protect both the intracellular and pericellular milieu of multicellular organisms from the collateral damage inflicted by promiscuous proteolysis and protection from cell death.

  • Publications

    1. Gosai SJ, Kwak JH, Luke CJ, Long OS, King DE, Kovatch KJ, Johnston PA, Shun TY, Lazo JS, Perlmutter DH, Silverman GA and Pak SC. Automated high –content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z. PLoS One 5(11): e15460, 2010.
    2. Luke Cliff J., Pak Stephen C., Askew Yuko 2. Luke CJ, Pak SC, Askew YS, Naviglia TL, Askew DJ, Nobar SM, Vetica AC, Long OS, Watkins SC, Stolz DB, Barstead RJ, Moulder GL, Bromme D, Silverman GA. An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of Lysosomal injury. Cell 130(6):1108-1119, 2007.
    3. Pak SC, Kumar V, Tsu C, Luke CJ, Askew YS, Askew DJ, Mills DR, Brömme D, Silverman, GA. SRP-2 is a cross-class inhibitor that participates in post-embryonic development of the nematode Caenorhabditis elegans: Initial Characterization of the Clade L Serpins. J Biol Chem 279(15): 15448-15459, 2004.
    4. Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PGW, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E. Salvesen FS, Travis J, Whisstock JC. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions and a revised nomenclature. J Biol Chem, 276(36): 33292-33296, 2001.

     

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