Drug Transporters and Na<sup>+</sup>/H<sup>+</sup>Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

Walsh, Dustin R.; Nolin, Thomas D.; Friedman, Peter A.

doi:10.1124/pr.115.010728

Cited by 17 publications

(13 citation statements)

References 237 publications

(319 reference statements)

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“…[11][12][13][14] The NHERF family of PDZ proteins are commonly expressed in polarized epithelia. 15 Abnormal expression of NHERF1 has been found in several types of tumors, such as hepatocellular carcinoma, breast cancer and nerve schwannoma. 14 NHERF1 expression is also related to cancer invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

et al. 2017

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Renal cell carcinoma (RCC) is one of the most aggressive urologic cancers, however, the mechanism on supporting RCC carcinogenesis is still not clear. By using gene expression profile analysis and functional clustering, PDZ domain-containing 1 (PDZK1) was revealed to be downregulated in human clear cell renal cell carcinoma (ccRCC) samples, which was also verified in several independent public ccRCC data sets. Using PDZK1 overexpression and knockdown models in ccRCC cell lines, we demonstrated that PDZK1 inhibited cell proliferation, cell cycle G1/S phase transition, cell migration and invasion, indicating a tumor-suppressor role in the development and progression of ccRCC. Our study further demonstrated that PDZK1 inhibited cell proliferation and migration of ccRCC via targeting SHP-1. PDZK1 was further identified to suppress cell proliferation by blocking SHP-1 phosphorylation at Tyr536 via inhibition of the association between SHP-1 and PLCβ3, and then retarding Akt phosphorylation and promoting STAT5 phosphorylation in ccRCC cells. Moreover, the inhibitive effects of PDZK1 on SHP-1 phosphorylation and the tumor growth were verified in vivo by xenograft tumor studies. Accordingly, PDZK1 expression was negatively correlated with SHP-1 activation and phosphorylation, advanced pathologic stage, tumor weight and size, and prognosis of ccRCC patients. These findings have provided first lines of evidences that PDZK1 expression is negatively correlated with SHP-1 activation and poor clinical outcomes in ccRCC. PDZK1 was identified as a novel tumor suppressor in ccRCC by negating SHP-1 activity.

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Section: Introductionmentioning

confidence: 99%

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

et al. 2017

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“…On the other hand, NHERF1 belongs to a superfamily of PDZ proteins which have been implicated in regulating the membrane abundance, localization, and function of a number of drug transporters [ 6 ]. NHERF1 was annotated to regulation of cell excretion in Gene Ontology ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…NHERF1 contains two N-terminal tandem PSD95/Dlg/ZO-1 (PDZ) domains followed by an ezrin–radixin–moesin (ERM)-binding region [ 5 ]. Through these domains, NHERF1 binds to ion transporters, G protein-couple receptors (GPCR), and cytoskeleton-associated proteins, thereby controlling internalization and trafficking of several receptors, ion channels, and transporters [ 6 ]. Moreover, NHERF1 has also been shown to interact with cancer-related proteins such as phosphatase and tensin homolog deleted on chromosome ten (PTEN), spleen tyrosine kinase (SYK), platelet-derived growth factor receptor (PDGFR), and epidermal growth factor receptor (EGFR), and modulate their downstream signaling [ 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells

Tao

Yang

Qin

et al. 2017

IJMS

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Cervical cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely utilized in locally advanced cervical cancer patients. However, resistance has been the major limitation. In this study, we found that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) was downregulated in cisplatin-resistant cells. Analysis based on a cervical cancer dataset from The Cancer Genome Atlas (TCGA) showed association of NHERF1 expression with disease-free survival of patients received cisplatin treatment. NHERF1 overexpression inhibited proliferation and enhanced apoptosis in cisplatin-resistant HeLa cells, whereas NHERF1 knockdown had inverse effects. While parental HeLa cells were more resistant to cisplatin after NHERF1 knockdown, NHERF1 overexpression in CaSki cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that NHERF1 significantly inhibited AKT and extracellular signal–regulated kinase (ERK) signaling pathways in cisplatin-resistant cells. Taken together, our results provide the first evidence that NHERF1 can sensitize cisplatin-refractory cervical cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumors.

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“…In general, ABC transporters consist of 6 to 17 transmembrane domains (TMD), one or more nucleotide‐binding domains (NBD), and one or more drug binding domains (Fig. ; L. Lin et al., ; Walsh, Nolin, & Friedman, ). The ABC efflux transporters are responsible for transporting a wide range of endogenous and exogenous substrates (Table ).…”

Section: Transportersmentioning

confidence: 99%

Overview of Transporters in Pharmacokinetics and Drug Discovery

Zhang

2018

CP Pharmacology

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Transporters play important roles in absorption, distribution, metabolism, and elimination (ADME) processes, as well as drug pharmacokinetics (PK) and pharmacodynamics (PD). They are also important in maintaining the homeostasis of endogenous compounds and nutrients in the body. Increasing evidences also suggest that they are important in mediating drug-drug interactions (DDIs). While the significance of transporters in drug pharmacodynamics and DDIs are beyond the scope of this overview, the basic concepts of transporters, their contributions in membrane permeation processes, and their roles in influencing drug ADME pathway and PK will be discussed. © 2018 by John Wiley & Sons, Inc.

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Drug Transporters and Na⁺/H⁺Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

Cited by 17 publications

References 237 publications

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells

Overview of Transporters in Pharmacokinetics and Drug Discovery

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Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

Cited by 17 publications

References 237 publications

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation

NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells

Overview of Transporters in Pharmacokinetics and Drug Discovery

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Product

Resources

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Drug Transporters and Na⁺/H⁺Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins