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J. Biol. Chem., Vol. 279, Issue 14, 14398-14408, April 2, 2004

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A WT1 Co-regulator Controls Podocyte Phenotype by Shuttling between Adhesion Structures and Nucleus^*

Manakan B. Srichai, Martha Konieczkowski, Aparna Padiyar, David J. Konieczkowski, Amitava Mukherjee, Patrick S. Hayden, Sweta Kamat, M. Ashraf El-Meanawy, Shenaz Khan, Peter Mundel, Sean Bong Lee¶, Leslie A. Bruggeman, Jeffrey R. Schelling||, and John R. Sedor**

From the Departments of Medicine and ^**Physiology and Biophysics, School of Medicine, Case Western Reserve University and Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, Ohio 44109-1998, the Department of Anatomy, Albert Einstein College of Medicine, Bronx, New York 10461, and the ^¶Department of the Genetics of Development, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

Glomerular podocyte differentiation state is critical for filtration barrier function and is regulated by WT1, a zinc finger transcription factor. A yeast two-hybrid assay identified a novel, WT1-interacting protein (WTIP) that maps to human chromosome 19q13.1, a region with genes linked to familial focal segmental glomerulosclerosis. The domain structure of WTIP is similar to the zyxin subfamily of cytosolic LIM domain-containing proteins, which contain three carboxyl-terminal LIM protein-protein interaction domains and a proline-rich, pre-LIM region with a nuclear export signal. Other LIM domain-containing proteins (zyxin and mouse muscle LIM protein) did not interact with WT1 in two-hybrid assays, and WTIP did not interact with an unrelated transcription factor, LMX1B. WTIP mRNA was detected in cultured podocytes and was developmentally regulated, with expression peaking in mouse kidney at embryonic day 15-16 (E15-E16) in kidney but persisting into adulthood. In situ hybridization demonstrated WTIP expression in developing E15 glomeruli and in cultured podocytes. The partial WTIP clone, which interacted with WTIP in the two-hybrid assay, co-localized with WT1 in nuclei, co-precipitated with WT1, and inhibited WT1-dependent transcriptional activation of the amphiregulin promoter. In contrast, full-length WTIP was excluded from cell nuclei, but after the addition of leptomycin B, an inhibitor of Crm1-mediated nuclear export, it accumulated in the nucleus and co-precipitated with WT1 in whole cell lysates. Epitope-tagged WTIP co-localized with the adaptor protein CD2AP (CMS) in podocyte actin spots and with Mena at cell-cell junctions. We propose that WTIP monitors slit diaphragm protein assembly as part of a multiple protein complex, linking this specialized adhesion junction to the actin cytoskeleton, and shuttles into the nucleus after podocyte injury, providing a mechanism whereby changes in slit diaphragm structure modulate gene expression.

Received for publication, December 24, 2003

^* This work was supported by National Institutes of Health Grants DK038558, DK07470, P50 DK054178, and DK064719 and the Kidney Foundation of Ohio. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| An Established Investigator of the American Heart Association.

To whom correspondence should be addressed: Dept. of Medicine, BG 531, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109-1998. Tel.: 216-778-4993; Fax: 216-778-8248; E-mail: jrs4{at}po.cwru.edu.

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