Signaling by nephrin requires the adaptor protein, Nck, and the actin nucleation-promoting factor, N-WASP, to stimulate actin polymerization necessary for efficient glomerular function. Disruptions to this signaling pathway result in nephrotic syndromes, which are characterized by abnormal secretion of protein into urine and ultimately end-stage renal failure. Clustering of the proteins, nephrin and Nck, have been suggested to be important for efficient signaling, though a mechanistic rationale for this is lacking. Studies from our lab have identified a novel regulation of N-WASP activity through dimerization, which increases N-WASP's activity in vitro by >100- fold. We hypothesize that Nck clustering regulates N-WASP dimerization in nephrin signaling, which we propose to study.

Public Health Relevance

The clustering of proteins has been suggested to be important for proper kidney function, by potentially regulating protein-activity. Two proteins, nephrin and Nck, are relevant to a spectrum kidney diseases that may ultimately lead to kidney failure. We propose that the clustering of the two proteins, nephrin and Nck, regulates the dimerization and activity of another protein, N-WASP, that is involved in the polymerization of actin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK091074-02
Application #
8325835
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M1))
Program Officer
Rankin, Tracy L
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Hung, Ruei-Jiun; Pak, Chi W; Terman, Jonathan R (2011) Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334:1710-3