
Cells reproduce by duplicating their genomes and other components and then distributing these components equally into two daughter cells. The carefully orchestrated series of events that leads to cell duplication and division is called the cell cycle. Cell-cycle events are timed and coordinated by a network of regulatory proteins called the cell-cycle control system.
The Morgan Lab's research goal is a detailed biochemical understanding of the proteins that make up the cell-cycle control system. Much of the research has focused on the cyclin-dependent protein kinases (Cdks). These highly conserved enzymes are activated at specific cell cycle stages and are directly responsible for triggering major cell cycle events such as DNA replication and mitosis. Members of the Morgan lab study the molecular mechanisms that govern progression through the cell division cycle using a variety of biochemical and genetic approaches, primarily in budding yeast, to study the cell biology and enzymology of two regulatory enzymes: the cyclin-dependent protein kinases and the ubiquitin ligase APC, particularly important in controlling mitosis.
The lab uses a variety of different model systems, including budding yeast and mammalian cells, to address fundamental questions in the control of cell division by Cdks and other regulatory molecules. Major projects in the lab include the following:
Targets of the Cdks: Little is known about the mechanisms by which Cdks trigger cell-cycle events. It is generally assumed that Cdks, like other protein kinases, exert their effects by phosphorylating target proteins, but few of these target proteins have been identified. The lab uses a novel 'chemical genetic' approach, conceived by our UCSF colleague Kevan Shokat, to search the yeast and vertebrate proteomes for Cdk substrates.
Exit from mitosis: Morgan Lab explores the regulatory mechanisms that complete the cell cycle in late mitosis. Much of this work focuses on a mysterious multi-subunit enzyme called the Anaphase-promoting complex (APC). The APC is a ubiquitin-protein ligase that catalyzes the attachment of the protein ubiquitin to substrate proteins, thereby targeting these substrates for destruction. In late mitosis, the APC triggers the proteolytic destruction of several cell-cycle regulators, including cyclins. The lab is interested in the biochemical reactions catalyzed by the APC and in the regulatory systems that control these reactions.
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Phosphoregulation of Phase Separation by the SARS-CoV-2Â N Protein Suggests a Biophysical Basis for its Dual Functions. Mol Cell. 2020 Nov 20. Carlson CR, Asfaha JB, Ghent CM, Howard CJ, Hartooni N, Safari M, Frankel AD, Morgan DO. PMID: 33248025.
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Polyanions provide selective control of APC/C interactions with the activator subunit. Nat Commun. 2019 12 20; 10(1):5807. Mizrak A, Morgan DO. PMID: 31862931.
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Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site. Nat Commun. 2019 11 15; 10(1):5189. Rosen LE, Klebba JE, Asfaha JB, Ghent CM, Campbell MG, Cheng Y, Morgan DO. PMID: 31729382.
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The pseudosubstrate inhibitor Acm1 inhibits the anaphase-promoting complex/cyclosome by combining high-affinity activator binding with disruption of Doc1/Apc10 function. J Biol Chem. 2019 11 15; 294(46):17249-17261. Qin L, Mizrak A, Guimarães DSPSF, Tambrin HM, Morgan DO, Hall MC. PMID: 31562243.
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Firing of Replication Origins Frees Dbf4-Cdc7 to Target Eco1 for Destruction. Curr Biol. 2017 Sep 25; 27(18):2849-2855.e2. Seoane AI, Morgan DO. PMID: 28918948.
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Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex. Mol Cell. 2016 10 06; 64(1):12-23. Davey NE, Morgan DO. PMID: 27716480.
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Quantitative framework for ordered degradation of APC/C substrates. BMC Biol. 2015 Nov 16; 13:96. Lu D, Girard JR, Li W, Mizrak A, Morgan DO. PMID: 26573515.
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An E2 accessory domain increases affinity for the anaphase-promoting complex and ensures E2 competition. J Biol Chem. 2015 Oct 02; 290(40):24614-25. Girard JR, Tenthorey JL, Morgan DO. PMID: 26306044.
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Multiple mechanisms determine the order of APC/C substrate degradation in mitosis. J Cell Biol. 2014 Oct 13; 207(1):23-39. Lu D, Hsiao JY, Davey NE, Van Voorhis VA, Foster SA, Tang C, Morgan DO. PMID: 25287299.
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Sgo1 recruits PP2A to chromosomes to ensure sister chromatid bi-orientation during mitosis. J Cell Sci. 2014 Nov 15; 127(Pt 22):4974-83. Eshleman HD, Morgan DO. PMID: 25236599.
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Activation of the APC/C ubiquitin ligase by enhanced E2 efficiency. Curr Biol. 2014 Jul 07; 24(13):1556-62. Van Voorhis VA, Morgan DO. PMID: 24930963.
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Cdk1-dependent phosphorylation of Iqg1 governs actomyosin ring assembly prior to cytokinesis. J Cell Sci. 2014 Mar 01; 127(Pt 5):1128-37. Naylor SG, Morgan DO. PMID: 24413167.
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The D box meets its match. Mol Cell. 2013 Jun 06; 50(5):609-10. Morgan DO. PMID: 23746347.
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The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation. Mol Cell. 2012 Sep 28; 47(6):921-32. Foster SA, Morgan DO. PMID: 22940250.
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Separase biosensor reveals that cohesin cleavage timing depends on phosphatase PP2A(Cdc55) regulation. Dev Cell. 2012 Jul 17; 23(1):124-36. Yaakov G, Thorn K, Morgan DO. PMID: 22814605.
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Ubiquitination of Cdc20 by the APC occurs through an intramolecular mechanism. Curr Biol. 2011 Nov 22; 21(22):1870-7. Foe IT, Foster SA, Cheung SK, DeLuca SZ, Morgan DO, Toczyski DP. PMID: 22079111.
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Protein-linked ubiquitin chain structure restricts activity of deubiquitinating enzymes. J Biol Chem. 2011 Dec 30; 286(52):45186-96. Schaefer JB, Morgan DO. PMID: 22072716.
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Dynamics of Cdk1 substrate specificity during the cell cycle. Mol Cell. 2011 Jun 10; 42(5):610-23. Kõivomägi M, Valk E, Venta R, Iofik A, Lepiku M, Morgan DO, Loog M. PMID: 21658602.
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Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. Mol Cell. 2011 May 06; 42(3):378-89. Lyons NA, Morgan DO. PMID: 21549314.
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Catalysis of lysine 48-specific ubiquitin chain assembly by residues in E2 and ubiquitin. Mol Cell. 2010 Aug 27; 39(4):548-59. Rodrigo-Brenni MC, Foster SA, Morgan DO. PMID: 20797627.
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The hidden rhythms of the dividing cell. Cell. 2010 Apr 16; 141(2):224-6. Morgan DO. PMID: 20403319.
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Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science. 2009 Sep 25; 325(5948):1682-6. Holt LJ, Tuch BB, Villén J, Johnson AD, Gygi SP, Morgan DO. PMID: 19779198.
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Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism. Mol Cell. 2009 Apr 10; 34(1):68-80. Matyskiela ME, Morgan DO. PMID: 19362536.
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Functionally distinct isoforms of Cik1 are differentially regulated by APC/C-mediated proteolysis. Mol Cell. 2009 Mar 13; 33(5):581-90. Benanti JA, Matyskiela ME, Morgan DO, Toczyski DP. PMID: 19285942.
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Mechanisms of ubiquitin transfer by the anaphase-promoting complex. J Biol. 2009; 8(10):92. Matyskiela ME, Rodrigo-Brenni MC, Morgan DO. PMID: 19874575.
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The anaphase-promoting complex promotes actomyosin-ring disassembly during cytokinesis in yeast. Mol Biol Cell. 2009 Feb; 20(4):1201-12. Tully GH, Nishihama R, Pringle JR, Morgan DO. PMID: 19109423.
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SnapShot: Cell-cycle regulators II. Cell. 2008 Nov 28; 135(5):974-974.e1. Morgan DO. PMID: 19041757.
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SnapShot: cell-cycle regulators I. Cell. 2008 Nov 14; 135(4):764-764.e1. Morgan DO. PMID: 19013283.
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Cyclin-specific control of ribosomal DNA segregation. Mol Cell Biol. 2008 Sep; 28(17):5328-36. Sullivan M, Holt L, Morgan DO. PMID: 18591250.
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Positive feedback sharpens the anaphase switch. Nature. 2008 Jul 17; 454(7202):353-7. Holt LJ, Krutchinsky AN, Morgan DO. PMID: 18552837.
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Modulation of the mitotic regulatory network by APC-dependent destruction of the Cdh1 inhibitor Acm1. Mol Cell. 2008 May 23; 30(4):437-46. Enquist-Newman M, Sullivan M, Morgan DO. PMID: 18498748.
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Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc Natl Acad Sci U S A. 2008 Feb 05; 105(5):1442-7. Blethrow JD, Glavy JS, Morgan DO, Shokat KM. PMID: 18234856.
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A coupled chemical-genetic and bioinformatic approach to Polo-like kinase pathway exploration. Chem Biol. 2007 Nov; 14(11):1261-72. Snead JL, Sullivan M, Lowery DM, Cohen MS, Zhang C, Randle DH, Taunton J, Yaffe MB, Morgan DO, Shokat KM. PMID: 18022565.
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Finishing mitosis, one step at a time. Nat Rev Mol Cell Biol. 2007 Nov; 8(11):894-903. Sullivan M, Morgan DO. PMID: 17912263.
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Identification of yeast IQGAP (Iqg1p) as an anaphase-promoting-complex substrate and its role in actomyosin-ring-independent cytokinesis. Mol Biol Cell. 2007 Dec; 18(12):5139-53. Ko N, Nishihama R, Tully GH, Ostapenko D, Solomon MJ, Morgan DO, Pringle JR. PMID: 17942599.
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Sequential E2s drive polyubiquitin chain assembly on APC targets. Cell. 2007 Jul 13; 130(1):127-39. Rodrigo-Brenni MC, Morgan DO. PMID: 17632060.
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A novel destruction sequence targets the meiotic regulator Spo13 for anaphase-promoting complex-dependent degradation in anaphase I. J Biol Chem. 2007 Jul 06; 282(27):19710-5. Sullivan M, Morgan DO. PMID: 17493939.
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Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell. 2007 Mar 09; 25(5):689-702. Holt LJ, Hutti JE, Cantley LC, Morgan DO. PMID: 17349956.
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Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase. Nat Cell Biol. 2007 Jan; 9(1):106-12. Woodbury EL, Morgan DO. PMID: 17173039.
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An architectural map of the anaphase-promoting complex. Genes Dev. 2006 Feb 15; 20(4):449-60. Thornton BR, Ng TM, Matyskiela ME, Carroll CW, Morgan DO, Toczyski DP. PMID: 16481473.
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The APC subunit Doc1 promotes recognition of the substrate destruction box. Curr Biol. 2005 Jan 11; 15(1):11-8. Carroll CW, Enquist-Newman M, Morgan DO. PMID: 15649358.
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Enzymology of the anaphase-promoting complex. Methods Enzymol. 2005; 398:219-30. Carroll CW, Morgan DO. PMID: 16275331.
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The Doc1 subunit is a processivity factor for the anaphase-promoting complex. Nat Cell Biol. 2002 Nov; 4(11):880-7. Carroll CW, Morgan DO. PMID: 12402045.
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Oscillation sensation. Nature. 2002 Aug 01; 418(6897):495-6. Morgan DO, Roberts JM. PMID: 12152065.
David Morgan earned his undergraduate degree in Animal Biology from the University of Calgary before pursuing a PhD in Endocrinology at University of California, San Francisco. He completed subsequent postdoctoral research at UCSF before joining the departments of Physiology and Biochemistry and Biophysics as a Professor.
Dr. Morgan is currently the Vice-Chair of the Department of Physiology as well as the Director of the UCSF Tetrad Graduate Program. He holds several awards including UCSF Medical School Teaching Award for Outstanding Lecture Series, UCSF Kaiser Award for Excellence in Teaching in the Classroom Setting. He holds the Jack D. and DeLoris Lange Endowed Chair in Physiology, and is a Royal Society of London Fellow.
Jonathan Asfaha, Graduate Student
Chris Carlson, Graduate Student
Nairi Hartooni, Graduate Student
Arda Mizrak, Graduate Student
Laura Rosen, Postdoctoral Fellow
Drew Thacker, Postdoctoral Fellow
Dora Scott, Executive Assistant