Carole Liedtke

Professor

Ph.D., Case Western Reserve University, 1980
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Intracellular Regulation of Cl Transport Proteins in Epithelial of Lung and Kidney

RESEARCH DESCRIPTION

The goal of my research is to understand how Na-K-Cl cotransport (NKCC1) and CFTR are activated during fluid secretion in epithelia. NKCC1 is an electroneutral transport pathway that is critical for supplying Cl for secretion and for mediating energy-efficient absorption of Na and Cl in renal tubules. I am dissecting signal transduction cascades involved in activation of NKCC1. My studies provided the first evidence for activation of NKCC1 cotransport 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 oligonucleotides targeted to specific PKC isotypes, we obtained compelling evidence for a critical role for PKC-delta isoform in regulation of NKCC1. Our current studies focus on protein-protein interactions involving a NKCC1 regulatory proteome. Proteins identified as binding partners in this proteome include F-actin, PKC-delta, protein phosphatase 2A, and stress-activated kinase SPAK. We are now investigating the regulatory proteome using techniques from protein biochemistry, mass spectrometry, cell physiology, bioinformatics and molecular biology.

PKC signalling has been implicated in the regulation of the Cl channel CFTR but with little detailed information on how PKC controls CFTR function. Rapid activation of CFTR is achieved through stimulation of beta-adrenergic receptors. We have demonstrated a pivotal role for a PKC-epsilon isoform during activation of CFTR. Our subsequent and current studies focus on protein-protein interactions that explain PKC regulation of CFTR. We have shown a unique role for protein-protein interactions involving PKC-epsilon binding to RACK1 and binding of RACK1 to NHERF at the PDZ1 domain. Our long term goal is to identify and characterize the target substrate for PKC-epsilon and learn how modification of the substrate regulates activation of CFTR.

RELATED RESEARCH AREAS

View Carole Liedtke's Publications on PubMed