Adam Frost

Assistant Professor of Biochemistry

Frost

B.S. Brigham Young University

M.D./Ph.D. Yale University

Research

References

frost@biochem.utah.edu

Adam Frost's Lab Page

Adam Frost's PubMed Literature Search

Research

Walls, fences, and barriers: these are the metaphors often used to describe the properties of cellular membranes. Yet, these "barriers" are dynamic structures that can bend, split, and fuse as cells remodel their stunning variety of shapes and internal forms. To accomplish this feat, cells use proteins to make, move, and shape membranes into the reaction surfaces and compartments that enable organelle biogenesis, intracellular membrane trafficking, cell division, and cell migration. Moreover, the mechanisms that control membrane morphology underlie cell-to-cell interactions and thus control development, infection, formation of syncytia, and immune responses.

My laboratory is searching for membrane remodeling factors and pathways using unbiased and genome-wide genetic screens in fission yeast. After identifying candidate genes, we employ a diversity of approaches to characterize the functions of the encoded proteins in vivo and in living human cells. Finally, we aim to extend our understanding of these proteins by reconstituting their membrane-associated states in vitro for functional assays and molecular structure determination by cryo-electron microscopy.

Presently, we are focused on two problems, both of which have direct relevance to cancer biology. First, we have discovered a network of interacting, tumor-suppressive proteins that regulates the homeostasis of lysosomes, autophagosomes and autophagy. More precisely, this pathway appears to regulate lysosome-to-lysosome fusion events, lysosome positioning and lysosome size. Now that we have identified many of the key genes in the pathway, we are seeking to elucidate the mechanisms by which they function in living cells and using model membranes in vitro. Second, we have discovered a conserved complex of membrane proteins in the Golgi that binds to key cell cycle checkpoint factors—including protein phosphatase type 2A—and manifests synthetic lethality with multiple factors involved in mitotic exit and cytokinesis. Our working model is that this complex forms a conserved PP2A holoenzyme that dephosphorylates crucial substrates upon nuclear envelope breakdown and the fragmentation of the Golgi that occurs during mitosis and throughout cytokinesis.

More broadly, we hope that our mechanistic and structural studies, when understood in the context of the genetic interactions we have mapped, will help us realize the clinical goal of combining drugs that avoid redundant mechanisms of action while exploiting synergistic means of killing malignant cells. Combination therapies are remarkably successful in containing HIV infection—even though HIV replicates and mutates far more rapidly than any malignant cell—so the rational design of combination therapies targeting synthetically lethal pathways should improve cancer chemotherapy.

References

  1. Koirala S, Guo Q, Kalia R, Bui HT, Eckert DM, Frost A, Shaw JM. Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):E1342-51
  2. Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS. A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell. 2012 Nov 21;151(5):1042-54
  3. Norman JF, Holmin JS, Beers AM, Cheeseman JR, Ronning C, Stethen AG, Frost AL. Aging and the discrimination of 3-D shape from motion and binocular disparity. Atten Percept Psychophys. 2012 Oct;74(7):1512-21
  4. Frost A, Elgort MG, Brandman O, Ives C, Collins SR, Miller-Vedam L, Weibezahn J, Hein MY, Poser I, Mann M, Hyman AA, Weissman JS. Functional repurposing revealed by comparing S. pombe and S. cerevisiae genetic interactions. Cell. 2012 Jun 8;149(6):1339-52
  5. Busath DD, Woodbury DJ, Frost A. Endosis and exosis: new names for fusion and budding. J Membr Biol. 2012 Nov;245(11):759-60
  6. Mim C, Cui H, Gawronski-Salerno JA, Frost A, Lyman E, Voth GA, Unger VM. Structural basis of membrane bending by the N-BAR protein endophilin. Cell. 2012 Mar 30;149(1):137-45
  7. Frost A. Membrane trafficking: decoding vesicle identity with contrasting chemistries. Curr Biol. 2011 Oct 11;21(19):R811-3
  8. Guerrier S, Coutinho-Budd J, Sassa T, Gresset A, Jordan NV, Chen K, Jin WL, Frost A, Polleux F. The F-BAR domain of srGAP2 induces membrane protrusions required for neuronal migration and morphogenesis. Cell. 2009 Sep 4;138(5):990-1004
  9. Frost A, Unger VM, De Camilli P. The BAR domain superfamily: membrane-molding macromolecules. Cell. 2009 Apr 17;137(2):191-6
  10. Frost A, Perera R, Roux A, Spasov K, Destaing O, Egelman EH, De Camilli P, Unger VM. Structural basis of membrane invagination by F-BAR domains. Cell. 2008 Mar 7;132(5):807-17
  11. Frost A, De Camilli P, Unger VM. F-BAR proteins join the BAR family fold. Structure. 2007 Jul;15(7):751-3
  12. Roux A, Uyhazi K, Frost A, De Camilli P. GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature. 2006 May 25;441(7092):528-31
  13. Papp L, McNeeley DF, Projan SJ, Bradford PA, Frost A, Nesin M. Recurrent episodes of shock-like syndrome caused by the same strain of vancomycin-resistant Enterococcus faecium in a pediatric patient. Microb Drug Resist. 2003 Fall;9(3):307-12
  14. Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J, Schlessinger J. The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol Cell. 2002 Oct;10(4):709-19
  15. Cole CD, Frost AS, Thompson N, Cotten M, Cross TA, Busath DD. Noncontact dipole effects on channel permeation. VI. 5F- and 6F-Trp gramicidin channel currents. Biophys J. 2002 Oct;83(4):1974-86

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Last Updated: 6/18/14