Adaptor, anchoring and scaffolding proteins play an important role in signaling transduction. In many situations, the interaction between signaling proteins is mediated by small amino acids sequences binding to specific proteins domains, such as src homology (SH), pTyr-binding (PTB) or PDZ domains. These interactions are responsible for determining location, function and activity of receptors and transporter proteins among others. We recently reported the isolation and partial characterization of two novel proteins MAP17 and PDZK1, both markedly upregulated in human carcinomas. PDZK1, isolated as a protein interacting with MAP17, contains four PDZ protein-interactions domains and therefore could potentially interacts with as many as four ligands. Using a combination of yeast two hybrid system and biochemical techniques, we have demonstrated that PDZK1 also interacts with the carboxy-terminal portion of cMOAT (MRP2), the canalicular multispecific organic anion transporter associated with multidrug resistance. Recent studies from other laboratories have confirmed the interactions of PDZK1 with MAP17 and cMOAT, and identified additional molecules interacting with PDZK1, such as the cystic fibrosis transmembrane conductance regulator (DFTR), the chloride channel CLC-3B, the type lla Na/Pi cotransporter and the high density lipoprotein (HDL) scavenger receptor SR-BI. We generated a PDZK1 knockout mouse which is characterized by increased serum cholesterol levels and markedly reduced expression of SR-BI in the liver, resulting in impaired "reverse cholesterol transport". These new findings define PDZK1 as a major player in the organization of a number of molecules including SR-BI, MAP17, CFTR, cMOAT and others. As a result, PDZK1 Is likely to play an important role in biological processes as diverse as lipid metabolism and cardiovascular disease, ion channel organization and multidrug resistance. The goals of this proposal are: 1) to generate a MAP17 knockout mouse to understand the role of MAP17 in regulating PDZK1 expression and lipoprotein metabolism, 2) to evaluate the role of PDZK1 in cardiovascular disease and the development of atherosclerosis by: a) Submitting PDZK1 knockout mice to high cholesterol diet and b) Generating apolipoprotein E (apoE)/PDZK1 and LDL receptor/PDZK1 double knockout mice, 3) to identify the putative molecular that plays the role of PDZK1 in the organization of SR-BI in steroidogenic organs.
Selected Recent Publications
Yesilaltay A, Kocher O, Rigotti A and Krieger M. Regulation of SR-BI-mediated high density lipoprotein metabolism by the tissue‑specific adaptor protein PDZK1. Curr Opin Lipidol, 16:147-152, 2005.
Capuano P, Basic D, Stange G, Hernando N, Kaissling B, Pal R, Kocher O, Biber J, Wagner CA and Murer H. Expression and regulation of the renal Na/phosphate cotransporter NaPi-IIa in a mouse model deficient for the PDZ protein PDZK1. Pflügers Archive European Journal of Physiology, 2005, 449:392-402.