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Sudha Shenoy

Associate Professor in Medicine, Assistant Professor in Cell Biology
(919) 681-5061
Research Interest: 
Membranes and organelles
Signal transduction
Research Summary: 
Dynamics and functional roles of post-translational modifications of seven-transmembrane G protein-coupled receptors and β-arrestins.
Research Description: 

Our lab is interested in understanding the roles of ubiquitination in G protein-coupled receptor trafficking and signal transduction. Both the receptor and the associated adaptor called β-arrestin become ubiquitinated in an agonist-dependent manner and in each case the modification directs a specific functional consequence: receptor ubiquitination allows the internalized receptor to be sorted into lysosomes for degradation, and β-arrestin ubiquitination allows efficient protein-protein interaction facilitating its multifaceted role in endocytosis and signaling. We have identified the cognate E3 ubiquitin ligases that ubiquitinate the β2 adrenergic receptor and β-arrestin2, and we have also identified the deubiquitinases (DUBs) that reverse these modifications. Current projects in the lab are aimed toward answering the following questions: (1) Is β-arrestin ubiquitination important for βAR signaling in the heart? (2) Does β-arrestin2 serve as a DUB adaptor in signaling? (3) Is DUB activity modulated upon GPCR activation, if so how? In addition to in vitro experimental systems, we are also working on transgenic and knockout mice to determine the physiological relevance of ubiquitination/deubiquitination dynamics in GPCR signaling.

The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization.
Berthouze M, Venkataramanan V, Li Y, Shenoy SK.
EMBO J. 2009. 28:1684-96.

Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ.
Proc Natl Acad Sci U S A. 2009. 106:6650-5.

Distinct roles for β-arrestin2 and arrestin-domain-containing proteins in β2 adrenergic receptor trafficking.
Han SO, Kommaddi RP, Shenoy SK.
EMBO Rep. 2013. 14:164-71.

MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.
Han SO, Xiao K, Kim J, Wu JH, Wisler JW, Nakamura N, Freedman NJ, Shenoy SK.
J Cell Biol. 2012. 199:817-30.

Beta2-adrenergic receptor lysosomal trafficking is regulated by ubiquitination of lysyl residues in two distinct receptor domains.
Xiao K, Shenoy SK.
J Biol Chem. 2011. 286:12785-95.