Research / Clinical Summary

Nai-Wen Chi, MD, PhD Associate Professor, Medicine Cancer Genetics Program Contact by Email

Protein PARsylation (poly-ADP-ribosylation) is increasingly appreciated as an important structural basis for the regulation of diverse physiological processes. This reversible modification is catalyzed by members of the PARP enzyme family and is well known for its role in mammalian genome stability.

PARsylation was previously thought to be confined to the nucleus, until my lab established its presence in the cytosol, particularly in the Golgi complex and underneath the plasma membrane. Our long-term goal is to fully explore PARsylation’s role in various cytosolic processes, including the targeting of vesicular proteins.

A vesicular protein of great clinical importance is GLUT4, the glucose transporter whose targeting is robustly regulated by insulin signaling. In unstimulated myocytes and adipocytes, most GLUT4 molecules are sequestered as a vesicular protein at/near the Golgi complex. In response to insulin stimulation, GLUT4 rapidly undergoes exocytic insertion into the plasma membrane, where it facilitates the diffusion of extracellular glucose into the cytosol. Defect in this insulin-regulated GLUT4 translocation leads to type 2 diabetes mellitus.

We recently reported the finding that the intracellular GLUT4 sorting and its exocytic competency depend on PARP-5 (also known as tankyrase) and particularly its PARsylating activity. This is based in part on the ability of tankyrase siRNA and pharmacological inhibitor to alter intracellular GLUT4 compartmentalization and to impair insulin-stimulated glucose uptake. In our working model, GLUT4-containing vesicles are modified at the Golgi by PARP-5, and the resultant PARsylation serves as a sorting tag that guides GLUT4 into exocytosis-competent compartments.

To further investigate tankyrase’s role in glucose homeostasis, we have recently knocked out the tankyrase gene in mice, and are actively characterizing the impact on glucose homeostasis and insulin action. The approaches taken include mouse physiology (glucose tolerance tests, insulin tolerance tests, glucose uptake assays), biochemistry (immunoblotting and other protein assays), cell biology (subcellular fractionation, immunofluorescence), and molecular biology (DNA transfection and adenovirus-mediated transduction).

Excerpt from PI’s CV

1986: MD, National Taiwan University (summa cum laude)

1994: Ph.D., Biochemistry, Harvard Medical School
Advisor: Richard Kolodner

1994-1997: Medical Resident and Endocrine Fellow
Massachusetts General Hospital, Harvard Medical School

1997-2000: Post-doctoral Fellow, Whitehead Institute/MIT
Advisor: Harvey Lodish

2000-2007: Assistant Professor and Attending Physician
Endocrine Division, Department of Medicine, UCSD

2007-present: Associate Professor and Attending Physician
Endocrine Division, Department of Medicine, UCSD


Partial list of recent publications:

• Yeh TY, Sbodio JI, Tsun ZY, Luo B, Chi NW (2007)
Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase.
Biochem J. 402:279

• Yeh TY, Sbodio JI, Chi NW (2006)
Mitotic phosphorylation of tankyrase, a PARP that promotes spindle assembly, by GSK3.
BBRC. 24;350

• Yeh TY, Meyer TN, Schwesinger C, Lee RM, Chi NW (2006)
Tankyrase recruitment to the lateral membrane in polarized epithelial cells: regulation by cell-cell contact and protein poly(ADP-ribosyl)ation.
Biochem J. 399:415

• Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM (2005)
JNK and TNF-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes.
J Biol Chem. 280:35361

• Yeh TY, Sbodio JI, Nguyen MT, Meyer TN, Lee RM, Chi NW (2005)
Tankyrase-1 overexpression reduces genotoxin-induced cell death by inhibiting PARP1.
Mol Cell Biochem. 276:183

• J. Sbodio, Chi NW (2002)
Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RxxPDG motif and is a novel tankyrase partner. J Biol Chem. 277:31887

• J. Sbodio Juan, Lodish HF, Chi NW (2002)
Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 and IRAP. Biochemical J. 361:451.

• Chi NW, Lodish HF (2000)
Tankyrase is a Golgi-Associated MAP Kinase Substrate that Interacts with IRAP in GLUT4 vesicles. J Biol Chem. 275:38437

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