Cancer, Enzymology, Protein Degradation, Signal Transduction
Multi-Disciplinary Training Areas
Cancer Biology [CAB], Pharmacology and Therapeutics Discovery [PTD]
PhD, Columbia University
Ubiquitin Signaling in Cancer Biology
Post-doctoral Fellow: Kenneth Wu
MD/PhD Graduate Student: Robert A. Chong
Covalent linkage of ubiquitin chains to cellular proteins leads to targeted substrate degradation by the 26S proteasome, thereby promoting unidirectional alteration of a divergent array of cellular processes, such as cell cycle progression and signal transduction, in a manner that profoundly impacts tumorigenesis.
Central to the ubiquitination reaction is the recognition of a substrate by an E3 ubiquitin protein ligase, which also functions to recruit an E2 ubiquitin-conjugating enzyme that catalyzes the transfer of ubiquitin to the target protein. Work from this laboratory has helped discover and characterize a super-family of E3s known as the cullin-RING ubiquitin ligases (CRL). CRL comprises ~300 modular protein complexes (including CRL1/SCF, CRL2-5 and CRL7), nearly half of E3s in humans. Lysine 48 (K48)-polyubiquitination mediated by CRL is a predominant cellular mechanism for targeting proteins for degradation by the 26S proteasome. CRL deregulation causes protein imbalance that contributes to myriad cellular defects or disease states such as cancer.
To understand and target K48 polyubiquitination by CRL, we recently developed fluorescence (Förster) resonance energy transfer (FRET)-based cell free reporter systems that generate a specific fluorescence signal as a result of enzymatic synthesis of an ubiquitin-ubiquitin covalent linkage through K48. On the basis of this assay format, we have performed high throughput screens, resulting in identification of a diversified array of small molecule inhibitors and are currently exploring their mechanisms of action and therapeutic potentials.
In addition, fluorescence-based assays are highly sensitive, allowing direct visualization of the process of K48 ubiquitination. We are exploring this innovation to develop real time reaction models that help understand the dynamics of K48 ubiquitination, a process of fundamental importance to a living cell.
Sarikas A, Xu X, Field LJ, Pan ZQ. The Cullin7 E3 ubiquitin ligase: a novel player in growth control. Cell Cycle 2008; 7(20): 3154-3161.
Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Field LJ, Wang R, Pan ZQ. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation . Mol. Cell 2008; 30: 403-414.
Yamoah Y, Oashi T, Sarikas A, Gazdoiu S, Osman R, Pan ZQ. Auto-inhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail. Proc.Natl. Acad. Sci USA 2005; 105(34): 12230-12235.
Gazdoiu S, Yamoah K, Wu K, Escalante CR, Tappin I, Bermudez V, Aggarwal AK, Hurwitz J, Pan ZQ. Proximity-induced activation of human Cdc34 through heterologous dimerization. Proc. Natl. Acad. Sci 2005; 102: 15053-15058.
Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K. Nedd8 on Cullin: Building an Expressway to Protein Destruction. Oncogene 2004 3; 15(23): 1985-1997.
Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A, Lee CG, Wei N, Wilkinson KD, Wang R, Pan ZQ. DEN1 is a dual function protease capable of processing the C-terminus of Nedd8 deconjugating hyper-neddylated CUL1. J Biol Chem 2003; 278: 28882-28891.
Dias DC, Dolios G, Wang R, Pan ZQ. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proc Natl Acad Sci USA 2002; 99(6): 16601-16606.
Wu K, Chen A, Pan ZQ. Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization. J Biol Chem 2000; 275: 32317-32324.
Tan P, Fuchs SY, Chen A, Wu K, Gomez C, Ronai Z, Pan ZQ. Recruitment of a ROC1:Cullin1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of IkBa. Mol Cell 1999; 3: 527-533.
Wu K, Kovacev J, Pan ZQ. Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Molecular cell 2010 Mar; 37(6).
Wu K, Chen A, Pan ZQ. Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization. The Journal of biological chemistry 2000 Oct; 275(41).
Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 2004 Mar; 23(11).
Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Nakajima HO, Field LJ, Wang R, Pan ZQ. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Molecular cell 2008 May; 30(4).
Wu K, Yan H, Fang L, Wang X, Pfleger C, Jiang X, Huang L, Pan ZQ. Mono-ubiquitination drives nuclear export of the human DCN1-like protein hDCNL1. The Journal of biological chemistry 2011 Sep; 286(39).
Xu X, Keshwani M, Meyer K, Sarikas A, Taylor S, Pan ZQ. Identification of the degradation determinants of insulin receptor substrate 1 for signaling cullin-RING E3 ubiquitin ligase 7-mediated ubiquitination. The Journal of biological chemistry 2012 Nov; 287(48).
Kovacev J, Wu K, Spratt DE, Chong RA, Lee C, Nayak J, Shaw GS, Pan ZQ. A SnapShot of Ubiquitin Chain Elongation: LYSINE 48-TETRA-UBIQUITIN SLOWS DOWN UBIQUITINATION. The Journal of biological chemistry 2014 Mar; 289(10).
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