- ADJUNCT ASSOCIATE PROFESSOR Medicine, Nephrology
PhD, The Rockefeller University
The Rockefeller University
Molecular Function of the WW Domain in Signaling and Diseases of the Kidney
Our goal is to elucidate signaling networks that use a modular protein domain, known as the WW domain, which mediates well-defined protein-protein interactions with proline motif-containing ligands. Missense point mutations mapped within the domain or its ligand have been implicated in several human diseases, including Liddle syndrome of hypertension and Golabi-Ito-Hall syndrome of intellectual disability. Our aim is to characterize signaling changes caused by genetic lesions that affect the WW domain complexes and result in human disease, with a special focus on diseases of the kidney. The ultimate goal of our research is to predict and design molecular tools for interventions in WW domain-mediated pathways to correct pathological states.
Two projects have been pursued in close collaboration between the Nephrology Division and the Sudol Laboratory: (I) In collaboration with Kirk Campbell, we are studying the role of the WW domain-containing protein YAP (Yes kinase-associated protein) in the biology of podocytes. YAP is a transforming gene of chromosome 11q22 amplicon, and its expression is elevated at a high frequency in human cancers, including cancers of liver, breast, ovary and prostate. YAP is also the main effector of a tumor suppressor pathway, known as HIPPO, which regulates a balance between cell proliferation and apoptosis. In podocytes, YAP exerts anti-apoptotic signaling. Understanding the mechanism of pro-survival function of YAP in podocytes shouldidentify new drug targets for management of kidney diseases, resulting from the loss of podocytes. (II) We have investigated the role of WW domain-containing proteins in the regulation of polycystin 1 (PKD1). In particular, we have identified Protein Kinase X as a modulator of PKD1-WW domain complex that assembles on the cytoplasmic tail of PKD1 and regulates embryonic development of the kidney.
Huang X, Poy F, Zhang R, Sudol M, Joachimiak A, Eck MJ. Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan. Nat Struct Biol. 2000 Aug ; 7(8): 634-8.
Chang A, Cheang S, Espanel X, Sudol M. Rsp5 WW domains interact directly with the carboxyl-terminal domain of RNA polymerase II. J Biol Chem. 2000 Jul 7; 275(27): 20562-71.
Sudol M, Hunter T. New wrinkles for an old domain. Cell 2000 Dec 22; 103(7): 1001-4.
Sliwa K , Russo T . Functions of WW domains in the nucleus. FEBS Lett. 2001 Feb 16; 490(3): 190-5.
Wu X, Chang A, Sudol M, Hanes SD. Genetic interactions between the ESS1 prolyl-isomerase and the RSP5 ubiquitin ligase reveal opposing effects on RNA polymerase II function. Curr Genet. 2001 Dec; 40(4): 234-42.
Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP. Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins. Biochemistry 2001 Dec 4; 40(48): 14585-92.
Espanel X . Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem. 2001 Apr 27; 276(17): 14514-23.
Macias MJ, Wiesner S, Sudol M. WW and SH3 domains, two different scaffolds to recognize proline-rich ligands. FEBS Lett. 2002 Feb 20; 513(1): 30-7.
Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003 Jan ; 11(1): 11-23.
Komuro A, Nagai M, Navin NE, Sudol M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003 Aug 29; 278(35): 33334-41.
Sudol M. From Rous sarcoma virus to plasminogen activator, src oncogene and cancer management. Oncogene 2011 Jul; 30(27).
Oka T, Schmitt AP, Sudol M. Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP. Oncogene 2012 Jan; 31(1).
Sudol M, Shields DC, Farooq A. Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Seminars in cell & developmental biology 2012 Sep; 23(7).
Li X, Hyink DP, Radbill B, Sudol M, Zhang H, Zheleznova NN, Wilson PD. Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse kidney development. Kidney international 2009 Jul; 76(1).
Campbell KN, Wong JS, Gupta R, Asanuma K, Sudol M, He JC, Mundel P. Yes-associated Protein (YAP) Promotes Cell Survival by Inhibiting Proapoptotic Dendrin Signaling. The Journal of biological chemistry 2013 Jun; 288(24).
Oka T, Sudol M. Nuclear localization and pro-apoptotic signaling of YAP2 require intact PDZ-binding motif. Genes to cells : devoted to molecular & cellular mechanisms 2009 May; 14(5).
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