- PROFESSOR Oncological Sciences
Ubiquitin Signaling in Cancer Biology
Post-doctoral Fellows: Kenneth Wu and Xinson Xu
Graduate Student: Jordan Kovacev
Covalent linkage of ubiquitin chains to cellular proteins leads to targeted degradation by the 26S proteasome, thus promoting unidirectional alteration of a divergent array of cellular processes that include cell cycle progression, signal transduction, and tumor suppression.
Central to the ubiquitination reaction are 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 uncovering a super-family of cullin-ROC1 RING based E3 ligases. We are focusing on SCF, the prototype of cullin-RING E3, with specific interest to understand the mechanisms by which it targets protein substrates for polyubiquitination and eventual proteasomal degradation. Given its broad spectrum of protein targets, the SCF pathway profoundly impacts a wide range of biological processes, including cell growth and death, development, signal transduction, transcriptional control, genomic integrity, and tumor suppression.
We have discovered an SCF-like E3 ligase complex containing CUL7, Fbw8, Skp1 and ROC1. Dysregulation of the CUL7 E3 Ligase has been directly linked to hereditary human diseases as cul7 germline mutations were found in patients with autosomal-recessive 3-M and Yakuts short stature syndromes, which are characterized by profound pre- and postnatal growth retardation. Recently, we have identified insulin receptor substrate 1, a critical mediator of insulin and insulin-like growth factor-1 signaling, as the proteolytic target of the CUL7 E3 ligase, suggesting a role for CUL7 as a novel growth regulator. We are currently exploring pathomechanistic insights into CUL7-linked growth retardation syndromes.
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).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Pan has not yet completed reporting of Industry relationships.
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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