I received my BA from Columbia University, New York, NY in 1961 and my MD degree from Boston University School of Medicine, Boston, MA in 1966. I trained in Internal Medicine at Montifiore Hospital Center, New York, NY and New York University Medical Center, New York, NY. I was a Post-Doctoral Fellow in Nephrology from 1969-1971 at Yale University School of Medicine, New Haven, CT. I have been on the faculty of Baylor College of Medicine, Houston (1973-1981), TX, University of Texas Medical School at Houston, Houston, TX (1981-1990), University California Los Angeles, Los Angeles, CA (1990-1995), West Virginia University School of Medicine, Morgantown, WV (1995-1999), Johns Hopkins University School of Medicine Baltimore, MD (1997-1998), and University of Maryland School of Medicine, Baltimore, MD (1999-present).
We have isolated and cloned two members of a protein family called the Sodium-Hydrogen Exchanger Regulatory Factor (NHERF-1 and NHERF-2). These proteins contain two tandem PDZ domains and a C-terminal ezrin-radixin-moesin-merlin binding domain. Recent studies have indicated that the NHERF proteins interact with a number of epithelial transporters including NHE3 (sodium-hydrogen exchanger type 3), Npt2a (type IIa sodium-phosphate co-transporter), ROMK (renal outer medullary potassium channel), and CFTR (cystic fibrosis transmembrane regulator); hormone receptors (beta2-adrenergic receptor, P2Y purinergic receptor, and the Platelet Derived Growth Factor Receptor); scaffolding proteins (ezrin, radixin, moesin, merlin); and signaling proteins (PKC, C-Yes associated protein). NHERF-1 knock-out mice demonstrated increased urinary excretion of phosphate, calcium, and uric acid associated with calcium deposition in the interstitium of the papilla of the kidney. Human mutations in NHERF-1 have been reported in aggressive forms of estrogen receptor positive breast cancer, psoriasis, schizophrenia, and nephrolitihiasis. We are currently characterizing the biologic role of the NHERF proteins on the activity and targeting NHE3, Npt2a, and other epithelial transporters to understand how NHERF mutations result in defined disease processes.
Lab Techniques and Equipment
Whole animal clearance and balance studies, primary cultures of renal proximal tubule cells, fluorescence measurement of cell pH, yeast 2-hybrid, biosensor analysis of protein-protein interactions, site directed mutagenesis, immunocytochemistry and confocal microscopy.
- Deborah Steplock, Laboratory Manager
- Shenolikar, S., Voltz, J., Minkoff, C.M., Wade, J., and Weinman, E.J. (2002) Targeted disruption of the mouse gene encoding a PDZ domain-containing protein adaptor, NHERF-1, promotes Npt2 internalization and renal phosphate wasting. Proc. Nat. Acad. Sci. USA 99:11470-11475.
- Weinman, E.J., Bodetti, A., Akom, M., Cunningham, R., Wang, F., Wang, Y., Liu, J., Steplock, D., Shenolikar, S., and Wade, J.B. (2003) NHERF-1 is required for renal adaptation to a low phosphate diet. Am. J. Physiol. Renal Physiol. 285: F1225-F1232.
- Cunningham, R., Steplock, D., Wang, F., Huang, H., E, X., Shenolikar, S., and Weinman, E.J. (2004) Defective PTH regulation of NHE3 activity and phosphate adaptation in cultured NHERF-/- renal proximal tubule cells. J. Biol. Chem. 279: 37815-37821.
- Shenolikar, S., Voltz, J.W., Cunningham, R., and Weinman, E.J. (2004) Regulation of ion transport by the NHERF family of PDZ proteins. Physiology 19: 48-54.
- Lee-Kwon, W., Wade, J.B., Pallone, T.L., and Weinman, E.J. (2005) Expression of TRPC 4 channel proteins that interact with NHER-2 in rat Descending Vasa Recta. Amer. J. Physiol. Cell Physiol. 288:C942-C949.
- Weinman, E.J., Cunningham, R., Wade, J.B., and Shenolikar, S. (2005) The Role of NHERF-1 in the Regulation of Renal Proximal Tubule Sodium-Hydrogen Exchanger 3 and Sodium-Dependent Phosphate Co-Transporter 2a. J. Physiol. 567:27-32.
- Wang, Y., Cai, H., Cebotaru, L., Hryciw, D., Weinman, E.J., Donowitz, M., Guggino, S.E., and Guggino, W.B. (2005) ClC-5: role in endocytosis in the proximal tubule. Amer. J. Physiol. Renal Physiol. 289:F850-F862.
- Khundmiri, S.J., Weinman, E.J., Steplock, D., Cole, J., Ahmad, A., Baumann, P.D., and Lederer, E.D. (2005) PTH regulation of renal proximal tubule Na+, K+ -ATPase requires the PDZ 1 domain of NHERF. J. Amer. Soc. Neph. 16:2598-2607.
- Bomberger, J.M., Spielman, W.S., Hall, C.S., Weinman, E.J. and Parameswaran, N. (2005) Differential trafficking of Adrenomedullin (AM) Receptor subtypes by Na+/H+ Exchanger Regulatory Factor-1 (NHERF-1). J. Biol. Chem. 280:23926-23935.
- Guerra, L., Fanelli, T., Favia, M., Riccardi, S., Busco, G., Cardone, R.A., Carrabino, S., Weinman, E.J., Reshkin, S.J., Conese, M., and Casavola, V. (2005) NHERF1 over-expression modulates CFTR activity in human airway 16HBE14o- cells and rescues ¿F508 CFTR functional expression in cystic fibrosis cells. J. Biol. Chem. 289:40925-40933.
- Cunningham, R., E, X., Steplock, D., Shenolikar, C. and Weinman, E.J. (2005) Defective PTH regulation of sodium-dependent phosphate transport in NHERF-1-/- renal proximal tubule cells and wild-type cells adapted to low phosphate media. Amer. J. Physiol. Renal Physiol. 289:F933-F938.
- Weinman, E.J., Cunningham, R., and Shenolikar, S. (2005) NHERF and Regulation of the Renal Sodium-Hydrogen Exchanger NHE3. Pflugers Archiv. 450:137-144.
- Donowitz, M., Milgram, S., Murer, H., Yun, C., and Weinman, E.J. (2005) Coming out of the NHERF family. J. Physiol. 567:1.
- Weinman, E.J., Mohanlal, V., Stoycheff, N., Wang, F., Steplock, D., Shenolikar, S., and Cunningham, R. (2006) Longitudinal Study of Urinary Excretion of Phosphate, Calcium, and Uric Acid in Mutant NHERF-1 Null Mice. Amer. J. Physiol. Renal Physiol. 290:F838-F843.
- Weinman, E.J., Hall, R.A., Friedman, P.A., Liu-Chen, L-Y., and Shenolikar S (2006) The Association of NHERF Adaptor Proteins with G-Protein-Coupled Receptors and Receptor Tyrosine Kinases. Annual Rev. Physiol. 68:491-505.
- Cunningham, R., Steplock, D., E, X., Biswas, R.S., Wang, F., Shenolikar, S., and Weinman, E.J. (2006 in press) Adenoviral expression of NHERF-1 in NHERF-1 null mouse renal proximal tubule cells restores Npt2a regulation by low phosphate media and parathyroid hormone. Amer. J. Physiol. Renal Physiol.
- Weinman, E.J., Mohanlal, V., Stoycheff, N., Wang, F., Steplock, D., Shenolikar, S., and Cunningham, R.: Longitudinal Study of Urinary Excretion of Phosphate, Calcium, and Uric Acid in Mutant NHERF-1 Null Mice. Amer. J. Physiol. Renal Physiol. (In press).
- Cunningham, R., Steplock, D., E, X., Biswas, R.S., Wang, F., Shenolikar, S., and Weinman, E.J.: Adenoviral expression of NHERF-1 in NHERF-1 null mouse renal proximal tubule cells restores Npt2a regulation by low phosphate media and parathyroid hormone. (Accepted).
- Capuano,P., Bacic,D, Roos, M., Sisler, S.M., Stange, G., Biber, J., Kaissling, B., Weinman, E.J., Shenolikar, S., Wagner, C.A., and Murer, H.: Defective coupling of apical PTH - receptors to phospholipase C prevents internalization of the Na+/phosphate cotransporter NaPi-IIa in NHERF1 deficient mice. (Submitted).