Disease relevance of PDZK1

• In this paper, we confirm the overexpression of PDZK1 in human carcinomas using a specific antibody and demonstrate the localization of the PDZK1 gene to human chromosome 1q21, a region frequently altered in neoplastic conditions [1].
• PDZK1 and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer [2].
• Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma [3].
• Activated in prostate cancer: a PDZ domain-containing protein highly expressed in human primary prostate tumors [4].
• While PDZ domain-containing proteins represent cellular targets for several different viral oncoproteins, including human papillomavirus E6, human T-cell leukemia virus type 1 Tax, and human adenovirus E4-ORF1, the functional consequences for such interactions have not been elucidated [5].

High impact information on PDZK1

• In the first cytosolic loop, the affected region is embedded between a putative G protein binding sequence and the site of phospholipid sensitivity, and in the COOH-terminal tail, splicing affects pump regulation by calmodulin, phosphorylation, and differential interaction with PDZ domain-containing anchoring and signaling proteins [6].
• SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells [7].
• Linking at least two CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity [8].
• We have identified a novel hydrophilic CFTR binding protein, CAP70, which is also concentrated on the apical surfaces [8].
• The Checkpoint Clamp Activates Mec1 Kinase during Initiation of the DNA Damage Checkpoint [9].

Biological context of PDZK1

• PDZK1 and a new gene, GREB1, demonstrated a significant correlation with ER phenotype in a panel of breast cancer cell lines [2].
• Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin [3].
• Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor [3].
• MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications [3].
• Finally, double transfection of OCTN2 with PDZK1 stimulated the uptake by OCTN2 of its endogenous substrate carnitine, and this increase could be accounted for by the 6-fold increase in transport capacity [10].

Anatomical context of PDZK1

• Interaction with PDZK1 is required for expression of organic anion transporting protein 1A1 on the hepatocyte surface [11].
• The interaction of PDZK1 with the C terminus of OCTN2 was also confirmed in a pull-down study using kidney brush-border membrane vesicles [10].
• In situ hybridization experiments showed that the expression of PDZK1 was limited to epithelial cells [12].
• PDZK1 is a 519-amino acid protein with a molecular weight of 63 kd; it is expressed in the kidney, pancreas, liver, gastrointestinal tract, and adrenal cortex [12].
• 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 [13].

Associations of PDZK1 with chemical compounds

• Taken together, the present study indicates the novel role of PDZK1 in regulating the functional activity of URAT1-mediated urate transport in the apical membrane of renal proximal tubules [14].
• A mutant SR-BI (SR-BIdel509) that lacked only the leucine in the PDZ-interacting domain failed to interact with PDZK1 in vitro, while showing normal selective uptake function in nonpolarized cells [15].
• PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2 [10].
• Transfection of PDZK1 increased the uptake of glycylsarcosine by PEPT2, whereas such stimulation was not observed for PEPT2 with the last four amino acids deleted [16].
• Alanine-scanning mutation in PEPT2 revealed the presence of a consensus sequence (-T-X-L) that is responsible for the PDZK1 interaction [16].

Physical interactions of PDZK1

• In an effort to elucidate the role of this interaction in vivo, the PDZK1-interacting domain of SR-BI was identified and mutated and expressed liver-specifically in mice [15].
• Results obtained by various in vitro analyses suggested that MAP17 interacts with the fourth domain of PDZK1 but not with other PDZ proteins localized in proximal tubular brush borders [17].
• PDZK1 directly interacts with PEPT2, exerting functional regulation of its transporting activity [16].
• The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3- exchanger DRA in rabbit small intestinal mucosa [18].
• Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C-terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain-containing proteins [19].

Co-localisations of PDZK1

• Immunohistochemical analysis indicated that OCTN1 was colocalized with PDZK1 on cell-surface, whereas colocalization with PDZK1-E195K was partially observed in cytoplasmic region [20].

Regulatory relationships of PDZK1

• Here we show that PDZK1 controls in a tissue-specific and post-transcriptional fashion the expression of SR-BI in vivo [21].
• Furthermore, we clarified the mechanism of enhanced glycylsarcosine (Gly-Sar) transport activity in PEPT2-expressing HEK293 cells after the PDZK1 coexpression [22].

Other interactions of PDZK1

• Unexpectedly, we found that hepatic overexpression of SPAP in mice resulted in liver deficiency of PDZK1 [23].
• Coimmunoprecipitation studies revealed that the wild-type URAT1, but not its mutant lacking the PDZ-motif, directly interacts with PDZK1 [14].
• Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3 [24].
• The interaction was recapitulated in HEK cells transfected with DRA and PDZK1, the human orthologue of CAP70 [18].
• A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications [3].

Analytical, diagnostic and therapeutic context of PDZK1

• Such an interaction requires the PDZ motif of URAT1 in its extreme intracellular C-terminal region and the first, second, and fourth PDZ domains of PDZK1 as identified by yeast two-hybrid assay, in vitro binding assay and surface plasmon resonance analysis (K(D) = 1.97-514 nM) [14].
• Using in situ hybridization, we demonstrated that MAP17 and PDZK1 mRNAs are markedly up-regulated in human carcinomas [1].
• This was confirmed by immunoprecipitation of an Oatp1a1-PDZK1 complex from cotransfected 293T cells as well as from native rat liver membrane extracts [11].
• Co-localization of interacting proteins with PDZK1 in proximal tubular cells was assessed by immunohistochemistry [25].
• Immunoelectron microscopy visualized both OCTN2 and PDZK1 in microvilli of absorptive epithelial cells [26].

References