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Deborah A Steplock M.S.

Academic Title: Faculty Research Assistant
Primary Appointment: Medicine
DSTEPLOC@MEDICINE.UMARYLAND.EDU
Location: BRB Room 8-027
Phone: (410) 706-1556
Fax: (410) 706-4669

Research Interests:

Our research efforts have focused on the regulation of renal electrolyte transport. Our specific interest has been in the regulation of the renal apical membrane sodium-hydrogen exchanger (NHE3) by cAMP. 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. They link NHE3 to the actin cytoskeleton thereby facilitating the phosphorylation and down regulation of NHE3 by forming a signal-complex with ezrin and protein kinase A. Recent studies have indicated that NHERF interacts with other epithelial transporters such as the sodium-bicarbonate co-transporter, type IIa sodium-phosphate co-transporter, renal outer medullary potassium channel, H+-ATP’ase, and the cystic fibrosis transmembrane regulator. In addition, NHERF-1 and NHERF2 interact with selected receptors (a2-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). Other experiments defined a role for the NHERF family of proteins in testicular differentiation and in the effect of estrogen in estrogen-receptor positive breast cancer cell lines. We are currently characterizing the biologic role of NHERF using knock-out mice and heterologous expression systems. The biochemistry and cellular trafficking of the NHERF proteins are being studied using expression systems, yeast 2-hybrid analyses, and by confocal microcroscopy. The potential role of NHERF in clinical renal diseases is being studied using archived renal biopsy material and immunocytochemistry.


Publications:

Weinman EJ, Mohanlal V, Stoycheff N, Wang F, Steplock D, Shenolikar S, Cunningham R.  Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Am J Physiol Renal Physiol. 2006 Apr;290(4):F838-43.

 

Khundmiri SJ, Weinman EJ, Steplock D, Cole J, Ahmad A, Baumann PD, Barati M, Rane MJ, Lederer E.   Parathyroid hormone regulation of NA+,K+-ATPase requires the PDZ 1 domain of sodium hydrogen exchanger regulatory factor-1 in opossum kidney cells. J Am Soc Nephrol. 2005 Sep;16(9):2598-607.

 

Cunningham R, E X, Steplock D, Shenolikar S, Weinman EJ. Defective PTH regulation of sodium-dependent phosphate transport in NHERF-1-/- renal proximal tubule cells and wild-type cells adapted to low-phosphate media. Am J Physiol Renal Physiol. 2005 Oct;289(4):F933-8.

 

Cunningham R, Steplock D, Wang F, Huang H, E X, Shenolikar S, Weinman EJ.   Defective parathyroid hormone regulation of NHE3 activity and phosphate adaptation in cultured NHERF-1-/- renal proximal tubule cells. J Biol Chem. 2004 Sep 3;279(36):37815-21.

 

Weinman EJ, Wang Y, Wang F, Greer C, Steplock D, Shenolikar S.   A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange. Biochemistry. 2003 Nov 4;42(43):12662-8.

 

Weinman EJ, Boddeti A, Cunningham R, Akom M, Wang F, Wang Y, Liu J, Steplock D, Shenolikar S, Wade JB.   NHERF-1 is required for renal adaptation to a low-phosphate diet. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1225-32.

 

Wade JB, Liu J, Coleman RA, Cunningham R, Steplock DA, Lee-Kwon W, Pallone TL, Shenolikar S, Weinman EJ.   Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse. Am J Physiol Cell Physiol. 2003 Dec;285(6):C1494-503.

 

Weinman EJ, Steplock D, Shenolikar S.   NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes. FEBS Lett. 2003 Feb 11;536(1-3):141-4.

 

Weinman EJ, Evangelista CM, Steplock D, Liu MZ, Shenolikar S, Bernardo A.   Essential role for NHERF in cAMP-mediated inhibition of the Na+-HCO3- co-transporter in BSC-1 cells. J Biol Chem. 2001 Nov 9;276(45):42339-46.

 

Weinman EJ, Steplock D, Shenolikar S. Acute regulation of NHE3 by protein kinase A requires a multiprotein signal complex. Kidney Int. 2001 Aug;60(2):450-4. Review.

 

Weinman EJ, Steplock D, Wade JB, Shenolikar S.   Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na(+)/H(+) exchange in OK cells. Am J Physiol Renal Physiol. 2001 Aug;281(2):F374-80.

 

Shenolikar S, Minkoff CM, Steplock DA, Evangelista C, Liu M, Weinman EJ. N-terminal PDZ domain is required for NHERF dimerization. FEBS Lett. 2001 Feb 2;489(2-3):233-6.