title: Targeted disruption of the PDZK1 gene by homologous recombination.
abstract: Proteins containing PDZ domains are involved in a large number of biological functions, including protein scaffolding, organization of ion channels, and signal transduction. We recently identified a novel PDZ domain-containing protein, PDZK1, that is selectively expressed in normal tissues, where it is associated and colocalized with MAP17, a small 17-kDa membrane-associated protein; cMOAT, an organic anion transporter implicated in multidrug resistance; and the type IIa Na/Pi cotransporter. The protein cluster formed by PDZK1, MAP17, and cMOAT is upregulated in a significant number of human carcinomas originating in the colon, breast, lung, and kidney. In order to better define the function of PDZK1 in the protein cluster and its potential role in the organization of ion channels, we generated a PDZK1 knockout mouse. While PDZK1-deficient mice developed normally, did not display any gross phenotypic abnormalities, and were fecund, lack of PDZK1 resulted in modulation of expression of selective ion channels in the kidney, as well as increased serum cholesterol levels. However, no significant redistribution of proteins known to interact with PDZK1, such as MAP17, cMOAT, and the type IIa Na/Pi cotransporter, was observed. The absence of a more significant phenotype in PDZK1-deficient mice may be due to functional compensation by other PDZ domain-containing proteins, which could be instrumental in determining the location of interacting proteins such as ion channels and other membrane-associated proteins in defined areas of the plasma membrane.
authors.affiliation: Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. okocher@caregroup.harvard.edu
authors.forename: Olivier
authors.initials: O
authors.lastname: Kocher
authors.forename: Rinku
authors.initials: R
authors.lastname: Pal
authors.forename: Mark
authors.initials: M
authors.lastname: Roberts
authors.forename: Christine
authors.initials: C
authors.lastname: Cirovic
authors.forename: Annalyn
authors.initials: A
authors.lastname: Gilchrist
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051398:Aquaporin 1; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D005818:Genetic Engineering / Q000379:methods*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D011995:Recombination, Genetic; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters / Q000235:genetics / Q000378:metabolism
chemical_list: D051398:Aquaporin 1; D020346:Aquaporins; D027202:Cationic Amino Acid Transporter 2; D002784:Cholesterol; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters; C496021:Aqp1 protein, mouse; C514896:PDZK1 protein, mouse; C509768:PDZK1IP1 protein, human; C509767:Pdzk1ip1 protein, mouse; C493555:Slc34a1 protein, mouse; C421109:multidrug resistance-associated protein 1