Adam Frost's Lab Page
Adam Frost's PubMed Literature Search
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.
1. Jackson M.E., Frost A., Moghaddam B. (2001) Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. Journal of Neurochemistry. 78:4 pp920-3. PMID: 11520912
2. *Cole, C.D., *Frost, A., Thompson, N., Cotten, M., Cross, T.A., & Busath, D.D. (2002) Noncontact Dipole Effects on Channel Permeation. VI. 5F- and 6F-Trp Gramicidin Channel Currents. Biophysical Journal 83:4 pp 1974-1986. *these authors contributed equally to this work. PMID: 12324416
3. Lax, I., Wong, A., Lamothe, B., Lee, A., Frost, A. , Hawes, J., & Schlessinger, J. (2002) The Docking Protein FRS2 Controls a MAP Kinase-Mediated Negative Feedback Mechanism for Signaling by FGF Receptors. M olecular Cell10 pp 709-719. PMID: 12419216 http://f1000.com/prime/1010369 F1 000 Prime Factor 2
4. Roux, A., Uyhazi, K., Frost, A., and De Camilli, P. (2006) GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature441, 528-531. PMID: 16648839 http://f1000.com/prime/1007616 F1 000 Prime Factor 10
5. Frost, A., De Camilli, P., and Unger, V. M. (2007). F-BAR Proteins Join the BAR Family Fold. Structure 15, 751-753. PMID: 17637334
6. Frost, A., Perera, R., Roux, A., Spasov, K., Egelman, E., De Camilli, P., and Unger, V. M. (2008) Structural Basis of Membrane Invagination by F-BAR Domains. Cell132, 807-817. PMID: 18329367 http://www.sciencedirect.com/science/article/pii/S0092867408002730 R esearch Highlight, Cell http://www.nature.com/nature/journal/v456/n7224/full/456842b.html R esearch Highlight, Nature http://f1000.com/prime/1103374 F100 0 Prime Factor 6
7. Frost, A., Unger, V. M. and De Camilli, P. (2009). Boomerangs, Bananas and Blimps: Structure and Function of F-BAR Domains in the Context of the BAR Domain Superfamily. The Pombe Cdc15 H omology Proteins . Landes Biosciences. Ed. Pontus Aspenström. ISBN: 978-1-58706-313-8
Bookshelf ID: NBK7021 http://www.landesbioscience.com/curie/chapter/3985/
8. Frost, A., Unger, V.M., and De Camilli, P. (2009) the BAR Domain Superfamily: Membrane-Molding Macromolecules. Cell 137, 191-196. PMID: 197379681
9. Guerrier, S., Coutinho-Budd, J., Sassa, T., Chen, K., Wei-Lin, J., Frost, A., and Polleux, P. (2009) T he F- BAR domain of srGAP2 induces membrane protrusions required for neuronal migration and morphogenesis . Cell138, 990-1004 (Cover) PMID: 19737524 http://www.sciencedirect.com/science/article/pii/S1534580709003505 R esearch Highlight, Cell http://f1000.com/prime/1163867 F1000 Prime Factor 4
10. Frost, A. (2011) Membrane Trafficking: decoding vesicle identity through contrasting chemistries. Current Biology Oct 11;21(19):R811-3. PMID: 21996503
11. Mim, C. Cui, H., Gawronski-Salerno, J.A., Frost, A., Lyman, E., Voth, G.A., and Unger, V.M. Structural Basis of Membrane Bending by the N-BAR Protein Endophilin. Cell (2012) 149, 137-145 PMID: 22464326
12. Busath D.D., Woodbury D.J., and Frost, A. Endosis and Exosis: New Names for Fusion and Budding. J Membrane Biology (2012) DOI 10.1007/s00232-012-9439-1PMID: 22653449
13. Frost A.*, Elgort M.G., Brandman O., Ives C., Collins S.R., Miller-Vedam L., Weibezahn J., Hein M.Y., Poser I., Mann M., Hyman A.A., Weissman J.S. Functional repurposing revealed by comparing S. pombe and S. cerevisiae genetic interactions. Cell (2012) Jun 8;149(6):1339-52 (Cover)
*Corresponding author PMID: 22682253 http://www.nature.com/nrg/journal/v13/n7/full/nrg3276.html Research Highlight, Nature Reviews Genetics
14. Brandman, O., Stewart-Ornstein, J., Wong, D., Larson, A., Williams, C.C., Li, G.W., Zhou, S., King, D., Shen, P.S., Weibezahn, J., Dunn, J.G., Rouskin, S., Inada, T., Frost, A.*, Weissman, J.S.* A Ribosome- Bound Quality Control Complex Triggers Degradation of Nascent Peptides and Signals Translation Stress. Cell (2012) Nov 21; 11(5):1042–1054 *Co-corresponding authors PMID: 23178123 http://www.nature.com/nrm/journal/v14/n1/full/nrm3499.html?WT.ec_id=NRM-201301 Research Highlight, Nature Reviews Molecular and Cellular Biology http://f1000.com/prime/717968380 F1000 Prime Factor 3
15. Koirala, S., Guo, Q., Kalia, R., Bui, H.T., Eckert, D.M., Frost, A.*, Shaw, J.M.* Interchangeable Adaptors Regulate Mitochondrial Dynamin Assembly for Membrane Scission. PNAS (2013) http://www.ncbi.nlm.nih.gov/pubmed/23530241 *Co-corresponding authors