Raymond J. Deshaies

Last updated
Raymond J. Deshaies
Born (1961-09-25) September 25, 1961 (age 62)
Waterbury, Connecticut
NationalityAmerican
Alma mater University of California, Berkeley (PhD)
Cornell University (BS)
Known forDiscoveries of cullin–RING ubiquitin ligases and elucidation of their mechanism of action and regulation, the JAMM family of ubiquitin isopeptidases, PROTACs (heterobifunctional small molecules that promote target degradation) the Sec61 translocon, and nucleolar sequestration as a regulatory mechanism. Founder of Proteolix, which developed carfilzomib/Kyprolis®
Scientific career
Fields Biochemistry, Cell Biology
Institutions Amgen
California Institute of Technology
Doctoral advisor Randy Schekman

Raymond Joseph Deshaies (born September 25, 1961) is an American biochemist and cell biologist. He is senior vice president of global research at Amgen and a visiting associate at the California Institute of Technology (Caltech). Prior to that, he was a professor of biology at Caltech and an investigator of the Howard Hughes Medical Institute. He is also the co-founder of the biotechnology companies Proteolix and Cleave Biosciences. His research focuses on mechanisms and regulation of protein homeostasis in eukaryotic cells, with a particular focus on how proteins are conjugated with ubiquitin and degraded by the proteasome.

Contents

Biography

Deshaies was born in Waterbury, Connecticut, on September 25, 1961. He graduated from Cornell University with a B.S. in biochemistry in 1983. He received his biochemistry doctorate from the University of California, Berkeley, in 1988. He performed postdoctoral studies at Berkeley (1988–1990) and subsequently at the University of California, San Francisco (1990–1994). He started as an assistant professor at Caltech in 1994 and was promoted to associate professor in 2000 and professor in 2005. In 2000, he was appointed as an assistant investigator of the Howard Hughes Medical Institute, and held the title of investigator from 2004–2017. He co-founded the biotechnology companies Proteolix and Cleave Biosciences in 2003 and 2011, respectively. He also founded the Proteome Exploration Laboratory at Caltech in 2006.

Scientific contributions

Protein translocation: As a graduate student and postdoctoral fellow working with Dr. Randy Schekman at the University of California, Berkeley, Deshaies discovered Sec61, which comprises the heart of the translocon that mediates insertion of secretory and membrane proteins into the endoplasmic reticulum of all eukaryotic cells. [1] [2] He went on to identify a complex of proteins that form the translocon in yeast cells. [3] In addition, Deshaies discovered a role for 70 kilodalton heat shock proteins (Hsp70s) in enabling the post-translational insertion of proteins into the endoplasmic reticulum and mitochondrial membranes. [4] This was the first specific, genetically- and biochemically-validated function to be discovered for a member of the Hsp70 family of proteins.

SCF and cullin–RING ubiquitin ligases: As a postdoctoral fellow working with Dr. Marc Kirschner at the University of California, San Francisco, Deshaies discovered a biochemical function for the ubiquitin-conjugated enzyme CDC34, which he showed mediates conjugation of ubiquitin onto G1 cyclin proteins in yeast cells. [5]

Upon starting his laboratory at Caltech, Deshaies studied the function of Cdc34 and how it relates to progression through the cell division cycle. These studies led his laboratory to discover the SCF complex SCFCdc4, [6] which is the progenitor of what is now known to be a large family of ~250 enzymes known as cullin–RING ubiquitin ligases (CRLs) that are conserved throughout eukaryotes and exert a major impact on the regulation of numerous cellular and organismal processes. [7] [8] In parallel, they established the paradigm of phosphorylation-dependent targeting of SCF substrates. [9] His lab went on to discover the critical catalytic subunit of SCFCdc4 (known as Rbx1/Roc1/Hrt1) and describe its mechanism of action. [10] Subsequent studies identified key aspects of CRL mechanism of action. [11] [12] [13] Particularly notable were their discoveries relating to the CRL regulators COP9 signalosome (CSN) and CAND1. In 2001-2002, the Deshaies lab showed that CSN, together with proteasome subunit Rpn11/PSMD14, are the founding members of a novel family of deubiquitinating enzymes. [14] [15] CSN plays a key role in regulating SCF and other CRL enzymes by removing the ubiquitin-like protein NEDD8 from their cullin subunit. [16] In 2013, they showed that Cand1 has the unusual property of being a ‘protein exchange catalyst’ that equilibrates F-box subunits of SCF ubiquitin ligases with the cullin scaffold subunit. [17]

Proteasome: The Deshaies group pioneered the use of affinity purification to rapidly purify and characterize the composition of eukaryotic proteasomes, leading to the discovery of a large number of factors, including Rpn13 and Ubp6, that interact with the proteasome in yeast cells. [18] In subsequent work they discovered that the Rpn11 subunit mediates removal of polyubiquitin chains from proteasome substrates as they are being degraded. [19]

P97/VCP: Early studies on p97 by the Deshaies group revealed a proteomic interaction network that includes all known UBX domain proteins, as well as a large number of ubiquitin ligase enzymes, including multiple CRLs. [20] These findings indicated that the biological roles of p97 were far broader than was thought at the time. This was followed by identifying novel functions for p97, including removal of proteins from chromatin as part of the DNA damage response [21] and extraction of stalled, nascent polypeptides from the ribosome. [22]

Drug development: Deshaies, in collaboration with Craig Crews (Yale), conceived the idea of using heterobifunctional small molecules, referred to as PROTACs, to tether cellular proteins to a ubiquitin ligase, resulting in ubiquitination and degradation of the tethered protein. [23] This concept underlaid the launch of the biotechnology companies Arvinas, C4 Therapeutics, Kymera, Oncopia, and Cullgen. The Deshaies group also identified small molecules that inhibit targeting of substrates to the proteasome [24] and removal of ubiquitin chains from substrates by Rpn11. [25] In addition, they discovered (in collaboration with Dr. Hugh Rosen of Scripps and Frank Schoenen of University of Kansas) the p97 inhibitors DBeQ [26] and ML240. [27] ML240 served as the basis for the development of CB-5083, [28] which entered human clinical trials in 2014.

Exit from mitosis: In addition to their studies on protein degradation, the Deshaies lab worked extensively on cell cycle control from 1994-2005, including studies on the regulation of exit from mitosis. They established the key paradigm that exit from mitosis is governed by the release of the protein phosphatase Cdc14 from its nucleolar anchor protein Net1 in late anaphase, which is triggered by the action of the mitotic exit network (MEN). [29] In later work, they established that an early step in the release of Cdc14 from Net1 is the phosphorylation of Net1 by the mitotic cyclin-Cdk complex [30]

Entrepreneurship

In 2003, Deshaies co-founded Proteolix with Dr. Craig Crews (Yale), Dr. Susan Molineaux, and Dr. Phil Whitcome (deceased), based on technology developed in the Crews and Deshaies labs. Dr. Lawrence Lasky, of Latterell Venture Partners, also played an instrumental role. Proteolix built on technology invented by Dr. Crews to develop carfilzomib/Kyprolis® through mid-phase 2 clinical trials before being acquired by Onyx in 2009. Kyprolis® was approved by the FDA in 2012 for treatment of multiple myeloma, and in 2013 Amgen acquired Onyx.

In 2011, Deshaies co-founded Cleave Biosciences with Dr. Seth Cohen (University of California, San Diego), Dr. Frank Parlati, Dr. Peter Thompson, and Dr. Laura Shawver, based on technology developed in the Cohen and Deshaies labs. Dr. Lawrence Lasky, this time at US Venture Partners, once again played an instrumental role. Cleave built on technology invented collaboratively by the Deshaies, Rosen (Scripps), and Schoenen (University of Kansas) laboratories to develop CB-5083, which is a potent and selective inhibitor of p97. CB-5083 entered human phase 1 clinical trials in 2014.

In May 2017, Deshaies resigned from the California Institute of Technology and Howard Hughes Medical Institute to accept the position of Senior Vice President for discovery research at Amgen. In 2018 he was appointed SVP for global research and is in charge of all research projects up through filing of an IND application.

Awards

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">SCF complex</span>

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">SKP2</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

<span class="mw-page-title-main">CUL1</span> Protein-coding gene in humans

Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.

<span class="mw-page-title-main">NEDD8</span>

NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.

<span class="mw-page-title-main">RBX1</span> Protein-coding gene in the species Homo sapiens

RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.

<span class="mw-page-title-main">CUL4A</span> Protein-coding gene in humans

Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">FBXW7</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.

<span class="mw-page-title-main">CDC34</span> Protein-coding gene in the species Homo sapiens

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

<span class="mw-page-title-main">CUL4B</span> Protein-coding gene in humans

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">PSMD14</span> Protein-coding gene in the species Homo sapiens

26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene. This protein is one of the 19 essential subunits of the complete assembled 19S proteasome complex. Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1, and Rpn12 form the lid sub complex of the 19S regulatory particle of the proteasome complex.

<span class="mw-page-title-main">Cullin</span> Hydrophobic scaffold protein

Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination.

<span class="mw-page-title-main">S-phase kinase-associated protein 1</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.

<span class="mw-page-title-main">Cell division control protein 4</span>

Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.

Michele Pagano is an Italian-American biochemist and cancer biologist best known for his work on cell cycle control and the ubiquitin-proteasome system. He is currently the chairman of the Department of Biochemistry and Molecular Pharmacology, and the Ellen and Gerald Ritter Professor of Oncology at the New York University School of Medicine. He is also an Investigator of the Howard Hughes Medical Institute. His laboratory has played a central role in elucidating the role of a family of enzymes, the cullin-RING ubiquitin ligases (CRLs), in mediating the proteolysis of key cellular regulators. In particular, his work has uncovered the molecular mechanisms by which CRLs control cell cycle progression, signal transduction pathways, and the DNA damage response. His work has also elucidated how the dysregulation of CRLs contributes to malignant transformation and metastasis, uncovering new therapeutic strategies.

References

  1. ↑ Deshaies, R.J., Fish, L.E., and Jagendorf, A.T. (1984). Permeability of chloroplast envelopes to Mg2+. Effects on protein synthesis. Plant Physiol. 74, 956-961
  2. ↑ Stirling, C.J., Rothblatt, J., Hosobuchi, M., Deshaies, R., and Schekman, R. (1992). Protein translocation mutants defective in the insertion of integral membrane proteins into the endoplasmic reticulum. Mol. Biol. Cell 3, 129-142
  3. ↑ Deshaies, R.J., Sanders, S., Feldheim, D., and Schekman, R. (1991). Assembly of yeast Sec proteins involved in translocation into the endoplasmic reticulum into a membrane-bound multisubunit complex. Nature 349, 806-808
  4. ↑ Deshaies, R.J., Koch, B.D., Werner-Washburne, M., Craig, E.A., and Schekman, R. (1988). A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 332, 800-805
  5. ↑ Deshaies, R.J., Chau, V., and Kirschner, M.W. (1995). Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. EMBO J. 14, 303-312
  6. ↑ Feldman, R.M.R., Correll, C.C., Kaplan, K.B., and Deshaies, R.J. (1997). A Complex of Cdc4, Skp1, and Cdc53/Cullin Catalyzes Ubiquitination of the Phosphorylated CDK Inhibitor Sic1. Cell 91, 221-230
  7. ↑ Petroski, M.D. and Deshaies, R. J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell. Biol. 6, 9-20
  8. ↑ Deshaies, R.J. and Joazeiro, C.A.P. (2009). RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399-434
  9. ↑ Verma, R., Annan, R., Huddleston, M., Carr, S., Reynard, G., and Deshaies, R.J. (1997). Phosphorylation of Sic1p by G1 cyclin/Cdk is required for its degradation and entry into S phase. Science 278, 455-460
  10. ↑ Seol, J.H., Feldman, R.M.R., Zachariae, W., Shevchenko, A., Correll, C.C., Lyapina, S., Chi, Y., Galova, M., Claypool, J., Sandmeyer, S., Nasmyth, K., Shevchenko, A., and Deshaies, R.J. (1999). Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev. 13, 1614-1626
  11. ↑ Petroski, M.D. and Deshaies, R.J. (2005). Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Cell 123, 1107-1120
  12. ↑ Pierce, N., Kleiger, G., Shan, S., and Deshaies, R.J. (2009). Detection of sequential ubiquitination on a millisecond time-scale. Nature 462, 615-619
  13. ↑ Kleiger, G., Saha, A., Lewis, S., Kuhlman, B., and Deshaies, R.J. (2009). Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell 139, 957-968
  14. ↑ Cope, G.A., Suh, G.S., Aravind, L., Schwarz, S.E., Zipursky, S.L., Koonin, E.V. and Deshaies, R.J. (2002). Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of NEDD8 from CUL1. Science 298, 608-611
  15. ↑ Verma, R., Aravind L., Oania, R., McDonald, W.H., Yates, J. R. III, Koonin, E.V. and Deshaies, R.J. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611-615
  16. ↑ Lyapina, S., Cope, G., Shevchenko, A., Serino, G., Tsuge, T., Zhou,C., Wolf, D.A., Wei, N., Shevchenko, A., and Deshaies, R.J. (2001). Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalsome. Science 18, 1382-1385
  17. ↑ Pierce, N.W., Lee, J.E., Liu, X., Sweredoski, M.J., Graham, R.L., Larimore, E.A., Rome, M., Zheng, N., Clurman, B.E., Hess, S., Shan, S.O., and Deshaies, R.J. (2013). Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins. Cell 153, 206-215
  18. ↑ Verma, R., Chen, S., Feldman, R., Schieltz, D., Yates, J., and Deshaies, R.J. (2000). Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11, 3425-39
  19. ↑ Verma, R., Aravind L., Oania, R., McDonald, W.H., Yates, J. R. III, Koonin, E.V. and Deshaies, R.J. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611-615
  20. ↑ Alexandru, G., Graumann, J., Smith, G.T., Kolawa, N.J., Fang, R., and Deshaies, R.J. (2008). UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1a turnover. Cell 134, 804-816
  21. ↑ Verma, R., Oania, R., Fang, R., Smith, G.T., and Deshaies, R.J. (2011). Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol. Cell 41, 82-92
  22. ↑ Verma, R., Oania, R.S., Kolawa, N.J., and Deshaies, R.J. (2013). Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. Elife 2, e00308
  23. ↑ Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.C., and Deshaies, R.J. (2001). Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 98, 8554-9
  24. ↑ Verma, R., Peters, N.R., Tochtrop, G.P., Sakamoto, K.M., D’Onofrio, M., Varadan, R., Fushman, D., Deshaies, R.J., and King, R.W. (2004). Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306, 117-120
  25. ↑ Li, J; Yakushi, T; Parlati, F; Mackinnon, AL; Perez, C; Ma, Y; Carter, KP; Colayco, S; Magnuson, G; Brown, B; Nguyen, K; Vasile, S; Suyama, E; Smith, LH; Sergienko, E; Pinkerton, AB; Chung, TDY; Palmer, AE; Pass, I; Hess, S; Cohen, SM; Deshaies, RJ (2017). "Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11". Nature Chemical Biology. 13 (5): 486–493. doi:10.1038/nchembio.2326. PMC   5570473 . PMID   28244987.
  26. ↑ Chou, T.F., Brown, S.J., Minond, D., Nordin, B.E., Li, K., Jones, A.C., Chase, P., Porubsky, P.R., Stoltz, B.M., Schoenen, F.J., Patricelli, M.P., Hodder, P., Rosen, H., and Deshaies, R.J. (2011) Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc. Natl. Acad. Sci. USA 108, 4834-4839
  27. ↑ Chou, T.F., Li, K., Frankowski, K.J., Schoenen, F.J., and Deshaies, R.J. (2013). Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. Chem. Med. Chem. 8, 297-312
  28. ↑ Anderson, D.J., Le Moigne, R., Djakovic, S., Kumar, B., Rice, J., Wong, S., Wang, J., Yao, B., Valle, E., Kiss von Soly, S., Madriaga, A., Soriano, F., Menon, M.K., Wu, Z.Y., Kampmann, M., Chen, Y., Weissman, J.S., Aftab, B.T., Jakes, F.M., Shawver, L., Zhou, H.J., Wustrow, D., and Rolfe, M. (2015). Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell 28, 653-665
  29. ↑ Shou, W., Seol, J.H., Shevchenko, A., Baskerville, C., Moazed, D., Chen, Z.W.S., Jang, J., Shevchenko, A., Charbonneau, H., and Deshaies, R.J. (1999). Exit from mitosis triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell 97, 233-244
  30. ↑ Azzam, R., Chen, S.L., Shou, W., Mah, A.S., Alexandru, G., Nasmyth, K., Annan, R.S., Carr, S.A., and Deshaies, R.J. (2004). Phosphorylation by cyclin B-Cdk underlies release of mitotic exit. Science 305, 516-519
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