Carol Liedtke, Ph.D.
Professor
cxl7@case.edu
BRB Room 824
(216) 368 4629 Phone
(216) 368 4223 Fax
Biography
In 1966 Carole Liedtke received her B.A. in Chemistry from Miami University. Dr. Liedtke was awarded her Ph.D. in 1980 from Case Western Reserve. She worked as a Post-doctoral fellow in Pediatrics and Pharmacology before becoming an Instructor, Assistant Professor in 1986, an Associate Professor in 1991 and a full Professor in 2000.
Research Interests
The goal of my research is to understand how Na-K-Cl cotransport (NKCC1) and CFTR are activated during fluid secretion. Epithelial NKCC1 is an electroneutral transport pathway that is critical for supplying Cl for secretion and for mediating energy-efficient absorption of Na and Cl. Studies of NKCC1 in epithelial cells and the nervous system exemplify the critical role of NKCC1 in cellular homeostasis. I am dissecting intracellular signalling cascades involved in activation of NKCC1 and CFTR. My studies provided the first evidence for activation of NKCC1 by alpha-adrenergic agonists, hyperosmotic stress and intracellular Cl. Subsequent investigation of membrane-associated events, including activation of phospholipases A2, C, and D, their regulation by G proteins, and generation of lipid mediators, led to more detailed study of protein kinase C (PKC) regulation of cotransport. Using antisense oligodeoxynucleotides to specific PKC isotypes, we obtained compelling evidence for a critical role for PKC-delta isoform in regulation of cotransport. Our current studies focus on protein-protein interactions between PKC-delta and cotransport protein or proteins associated with the cotransporter. Long term goals are to study structure-function relationships using simple deletions, truncations and site-specific mutagenesis and determine the impact of mutagenized protein in model systems. In addition, ongoing studies focus on the identification and characterization of serine/threonine protein phosphatase(s) that deactivate cotransport through protein dephosphorylation. Our interest here is to determine critical sites of phosphorylation ofNKCC1 cotransport protein.
PKC signalling has been implicated in the regulation of cystic fibrosis transmembrane regulator (CFTR) but with little detailed information on the role of PKC in controlling CFTR function. Using antisense technology, Dr. Liedtke demonstrated a pivotal role for PKC-epsilon isoform during activation of CFTR by cAMP. Subsequent and current studies focus on protein-protein interactions that explain PKC regulation of CFTR. Progress thus far indicates that PKC-epsilon binds to a PKC-receptor RACK1 and RACK1 binds to NHERF, a protein that binds to CFTR and is involved in the regulation of Na/H exchange. Downregulation of RACK1 results in loss of expression of CFTR in the apical plasma membrane, indicating a key role for RACK1 in stabilizing plasma membrane expression of CFTR. Our goal now is to identify and characterize sites of interaction between RACK1 and CFTR, the role of an interaction between filamin-A and RACK1 in stable expression of CFTR in the apical plasma membrane, and the role of PKC-epsilon in these interactions.
Publications
Smith L, Smallwood N, Altman A, Liedtke CM
"PKCdelta acts upstream of SPAK in the activation of NKCC1 by hyperosmomtic stress in airway epithelial cells"
J Biol Chem. 2008 Jun 11. [Epub ahead of print]
Auerbach M, Wang X, Liedtke CM
"Role of the scaffold protein RACK1 in apical expression of CFTR."
Am J Physiol Cell Physiol. 2007 Jul;293(1):C294-304.
Liedtke CM, Wang X
"The N-terminus of the WD5 repeat of human RACK1 binds to airway epithelial NHERF1"
Biochemistry. 2006 Aug 29;45(34):10270-7
Liedtke CM, Wang X, Smallwood ND
"Role for protein phosphatase 2A in the regulation of Calu-3 epithelial Na+-K+-2Cl-, type 1 co-transport function"
J Biol Chem. 2005 Jul 8;280(27):25491-8
Smallwood ND, Hausman BS, Wang X, Liedtke CM
"Involvement of NH2 terminus of PKC-delta in binding to F-actin during activation of Calu-3 airway epithelial NKCC1"
Am J Physiol Cell Physiol. 2005 Apr;288(4):C906-12
Liedtke CM, Raghuram V, Yun CC, Wang X
"Role of a PDZ1 domain of NHERF1 in the binding of airway epithelial RACK1 to NHERF1"
Am J Physiol Cell Physiol. 2004 May;286(5):C1037-44
Liedtke CM, Hubbard M, Wang X
"Stability of actin cytoskeleton and PKC-delta binding to actin regulate NKCC1 function in airway epithelial cells"
Am J Physiol Cell Physiol. 2003 Feb;284(2):C487-96
Liedtke CM, Yun CH, Kyle N, Wang D
"Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor"
J Biol Chem. 2002 Jun 21;277(25):22925-33
Liedtke CM, Papay R, Cole TS
"Modulation of Na-K-2Cl cotransport by intracellular Cl(-) and protein kinase C-delta in Calu-3 cells"
Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L1151-9
Liedtke CM, Cole TS
"Activation of NKCC1 by hyperosmotic stress in human tracheal epithelial cells involves PKC-delta and ERK"
Biochim Biophys Acta. 2002 Feb 13;1589(1):77-88
Liedtke CM, Cody D, Cole TS
"Differential regulation of Cl- transport proteins by PKC in Calu-3 cells"
Am J Physiol Lung Cell Mol Physiol. 2001 Apr;280(4):L739-47
Liedtke CM, Cole TS
"PKC signaling in CF/T43 cell line: regulation of NKCC1 by PKC-delta isotype"
Biochim Biophys Acta. 2000 Jan 10;1495(1):24-33
Liedtke CM, Cole TS
"Antisense oligonucleotide to PKC-epsilon alters cAMP-dependent stimulation of CFTR in Calu-3 cells"
Am J Physiol. 1998 Nov;275(5 Pt 1):C1357-64
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