Peptide binding consensus of the NHE‐RF‐PDZ1 domain matches the C‐terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)

Wang, Shusheng; Raab, Ronald W.; Schatz, Peter J.; Guggino, William B.; Li, Min

doi:10.1016/s0014-5793(98)00402-5

Cited by 265 publications

(243 citation statements)

References 18 publications

(34 reference statements)

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“…NHERF contains two tandem PDZ domains (PDZDs) at its NH 2 -terminus that have been shown to interact with a variety of proteins (Hall et al, 1998;Wang et al, 1998;Mohler et al, 1999;Weinman et al, 2000), and a MERLIN-binding motif at its COOHterminus. Wild-type PDZDs of NHERF were shown to bind to GST-IDB but not GST itself, confirming the physical binding of the two molecules ( Figure 1c).…”

Section: Confirmation Of Nherf and Syk Interactionmentioning

confidence: 99%

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

et al. 2004

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Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na + /H + exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na + /H + exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in B3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH 2 -terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.

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Section: Confirmation Of Nherf and Syk Interactionmentioning

confidence: 99%

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

et al. 2004

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“…For example, PMCA2b, but not PMCA4b, binds to NHERF2 which is a member of a small subfamily of PDZ proteins involved in membrane trafficking, anchoring, and regulation of ion transporters and receptors including Na ϩ /H ϩ exchanger-3 (15), ␤ 2 -adrenergic receptor (16), and the cystic fibrosis transmembrane conductance regulator (17,18). The differential localization of PMCA2b and PMCA4b might therefore be dependent upon different protein-protein interactions by their COOH-terminal tails.…”

Section: Differential Targeting Of Pmca Isoforms In Polarized Mdckmentioning

confidence: 99%

Alternative Splicing of the First Intracellular Loop of Plasma Membrane Ca2+-ATPase Isoform 2 Alters Its Membrane Targeting

Chicka¹,

Strehler

2003

Journal of Biological Chemistry

100

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Plasma membrane Ca 2؉ -ATPases (PMCAs) are involved in local Ca 2؉ signaling and in the spatial control of Ca 2؉ extrusion, but how different PMCA isoforms are targeted to specific membrane domains is unknown. In polarized MDCK epithelial cells, a green fluorescent protein-tagged PMCA4b construct was targeted to the basolateral membrane, whereas a green fluorescent protein-tagged PMCA2b construct was localized to both the apical and basolateral domain. The PDZ protein-binding COOH-terminal tail of PMCA2b was not responsible for its apical membrane localization, as a chimeric pump made of an NH 2 -terminal portion from PMCA4 and a COOH-terminal tail from PMCA2b was targeted to the basolateral domain. Deletion of the last six residues of the COOH terminus of either PMCA2b or PMCA4b did not alter their membrane targeting, suggesting that PDZ protein interactions are not essential for proper membrane localization of the pumps. Instead, we found that alternative splicing affecting the first cytosolic loop determined apical membrane targeting of PMCA2. Only the "w" form, which contains a 45-amino acid residue insertion, showed prominent apical membrane localization. By contrast, the x and z splice variants containing insertions of 14 and 0 residues, respectively, localized to the basolateral membrane. The w splice insert was the crucial determinant of apical PMCA2 localization, and this was independent of the splice configuration at the COOH-terminal end of the pump; both PMCA2w/b and PMCA2w/a showed prominent apical targeting, whereas PMCA2x/b, PMCA2z/b, and PMCA2z/a were confined to the basolateral membrane. These data report the first differential effect of alternative splicing within the first cytosolic loop of PMCA2 and help explain the selective enrichment of specific PMCA2 isoforms in specialized membrane compartments such as stereocilia of auditory hair cells.Plasma membrane Ca 2ϩ -ATPases (PMCAs) 1 constitute the major high affinity Ca 2ϩ extrusion system of eukaryotic cells.Their function is crucial for the maintenance of the normally low cytosolic free Ca 2ϩ levels ([Ca 2ϩ ] i ) in resting cells and to counteract the transient increases in [Ca 2ϩ ] i generated during Ca 2ϩ signaling (1, 2). The spatially and temporally distinct demands on Ca 2ϩ influx and efflux mandate the proper spatial distribution and abundance of the PMCAs across the plasma membrane. This is of particular importance in polarized cells such as neurons or epithelial cells where Ca 2ϩ signaling often must be restricted to the pre-and post-synaptic membrane (neurons) or where Ca 2ϩ influx and efflux must be spatially segregated between the apical and basolateral membrane (Ca 2ϩ transporting epithelia). However, the molecular determinants and the mechanisms by which PMCAs are targeted to distinct membrane domains are unknown.Mammalian PMCAs are encoded by four separate genes giving rise to PMCA isoforms 1-4. Isoform complexity is further enhanced by alternative splicing of the primary transcripts, such that over 20 distinct PMCA variants ...

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“…Deletion of a hydrophobic patch ( 1413 FLVI) ablates posttranslational folding (9), whereas truncating 70 (⌬70 CFTR) or more amino acid residues destabilizes the mature, complex-glycosylated CFTR (10,11). Finally, high affinity association of multivalent PDZ domain-containing molecules with the conserved C-terminal peptide ( 1476 DTRL) has been demonstrated (12)(13)(14).…”

mentioning

confidence: 99%

“…NHERF, the first protein to be reported to bind the C terminus of CFTR (12,18,19), contains two Class I PDZ domains (D1 and D2) and a C-terminal ERM-binding domain (20,21). The D1 and D2 domains bind with nanomolar affinity to the PDZbinding motifs of CFTR ( 1477 DTRL) and to the C terminus of other transport proteins, signaling molecules, and receptors (18,(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

The Role of the C Terminus and Na+/H+ Exchanger Regulatory Factor in the Functional Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Nonpolarized Cells and Epithelia

Benharouga

Sharma

et al. 2003

Journal of Biological Chemistry

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The conserved C-terminal peptide motif ( 1476 DTRL) of the cystic fibrosis transmembrane conductance regulator (CFTR) ensures high affinity binding to different PSD-95/Disc-large/zonula occludens-1 (PDZ) domaincontaining molecules, including the Na ؉ /H ؉ exchanger regulatory factor (NHERF)/ezrin-radixin-moesin-binding phosphoprotein of 50 kDa. The physiological relevance of NHERF binding to CFTR is not fully understood. Individuals with mutations resulting in premature termination of CFTR (S1455X or ⌬26 CFTR) have moderately elevated sweat Cl ؊ concentration, without an obvious lung and pancreatic phenotype, implying that the CFTR function is largely preserved. Surprisingly, when expressed heterologously, the ⌬26 mutation was reported to abrogate channel activity by destabilizing the protein at the apical domain and inducing its accumulation at the basolateral membrane

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Peptide binding consensus of the NHE‐RF‐PDZ1 domain matches the C‐terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)

Cited by 265 publications

References 18 publications

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

Alternative Splicing of the First Intracellular Loop of Plasma Membrane Ca2+-ATPase Isoform 2 Alters Its Membrane Targeting

The Role of the C Terminus and Na+/H+ Exchanger Regulatory Factor in the Functional Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Nonpolarized Cells and Epithelia

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