Characterization of a Di-leucine–based Signal in the Cytoplasmic Tail of the Nucleotide-pyrophosphatase NPP1 That Mediates Basolateral Targeting but not Endocytosis

Bello, Valérie; Goding, James W.; Greengrass, Vicki; Sali, Adnan; Dubljevic, Valentina; Lenoir, Christelle; Trugnan, Germain; Maurice, Michèle

doi:10.1091/mbc.12.10.3004

Cited by 54 publications

(58 citation statements)

References 59 publications

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“…In PSMA, mutation of the first leucine did not change significantly the internalization kinetics. Moreover, in polarized epithelial cells, proteins with di-leucine motif are targeted to the basolateral plasma membrane (Sheikh and Isacke, 1996;El Nemer et al, 1999;Bello et al, 2001). By contrast, PSMA is targeted to the apical plasma membrane in Madin-Darby canine kidney cells (Christiansen et al, 2003) and swapping the cytoplasmic tail of PSMA with the cytoplasmic tail of a di-leucine motif containing protein redirected PSMA to the basolateral plasma membrane (our unpublished data).…”

Section: Discussionmentioning

confidence: 79%

A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen

Rajasekaran

Gopalakrishnapillai

Oshima

et al. 2003

MBoC

190

147

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Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostate cancer and in tumor-associated neovasculature. In this study, we report that PSMA is internalized via a clathrin-dependent endocytic mechanism and that internalization of PSMA is mediated by the five N-terminal amino acids (MWNLL) present in its cytoplasmic tail. Deletion of the cytoplasmic tail abolished PSMA internalization. Mutagenesis of N-terminal amino acid residues at position 2, 3, or 4 to alanine did not affect internalization of PSMA, whereas mutation of amino acid residues 1 or 5 to alanine strongly inhibited internalization. Using a chimeric protein composed of Tac antigen, the ␣-chain of interleukin 2-receptor, fused to the first five amino acids of PSMA (Tac-MWNLL), we found that this sequence is sufficient for PSMA internalization. In addition, inclusion of additional alanines into the MWNLL sequence either in the Tac chimera or the full-length PSMA strongly inhibited internalization. From these results, we suggest that a novel MXXXL motif in the cytoplasmic tail mediates PSMA internalization. We also show that dominant negative 2 of the adaptor protein (AP)-2 complex strongly inhibits the internalization of PSMA, indicating that AP-2 is involved in the internalization of PSMA mediated by the MXXXL motif. INTRODUCTIONProstate-specific membrane antigen (PSMA) was originally identified by the monoclonal antibody (mAb) 7E11-C5 raised against the human prostate cancer cell line LNCaP (Horoszewicz et al., 1987). Subsequently, the PSMA gene was cloned (Israeli et al., 1993) and mapped to chromosome 11q (Rinker-Schaeffer et al., 1995). PSMA is a type II membrane protein with a short cytoplasmic N-terminal region (19 amino acids), a transmembrane domain (24 amino acids), and a large extracellular C-terminal portion (707 amino acids) (Israeli et al., 1993) with several potential N-glycosylation sites. Recently, it has been shown that PSMA is homologous to glutamate carboxypeptidase II (85% at nucleic acid level) isolated from rat brain (Coyle, 1997) and has folate hydrolase activity (Pinto et al., 1996;Halsted et al., 1998), and N-acetylated ␣-linked acidic dipeptidase (NAALDase) activity (Carter et al., 1996. The extracellular domain of PSMA shows homology (26% identity at the amino acid level) to the transferrin receptor I (Israeli et al., 1993) and to a recently cloned transferrin receptor II (Kawabata et al., 1999). The functional significance of homology between PSMA and transferrin receptor is not known.PSMA has been the subject of increasing interest in cancer research due to its potential as a diagnostic and therapeutic target for human prostate cancer (Chang et al., 1999a). PSMA is abundantly expressed in prostate cancer cells. Its expression is further increased in higher-grade cancers, metastatic disease, and hormone-refractory prostate carcinoma (Wright et al., 1996;Silver et al., 1997). In addition, PSMA has become the focus of even more intense interest due to the recent findings that it ...

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Section: Discussionmentioning

confidence: 79%

A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen

Rajasekaran

Gopalakrishnapillai

Oshima

et al. 2003

MBoC

190

147

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“…Incubations with primary and secondary antibodies were performed as described. 22 Nuclei were stained with propidium iodide. Confocal imaging was acquired with a Leica TCS SP2 Laser Scanning Spectral system attached to a Leica DMR inverted microscope with a 63/1.4 immersion objective.…”

Section: Methodsmentioning

confidence: 99%

A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature #

et al. 2009

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease characterized by early onset of cholestasis that leads to cirrhosis and liver failure before adulthood. PFIC3 may be improved by chronic administration of ursodeoxycholic acid, although in many cases liver transplantation is the only therapy. The disease is caused by mutations of the adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4) [multidrug resistance 3 (MDR3)] gene encoding a specific hepatocellular canalicular transporter involved in biliary phosphatidylcholine secretion. Several mutations have been reported; however, the effect of individual mutations has not been investigated. ABCB4 is highly homologous to ATP-binding cassette, sub-family B, member 1 (ABCB1) (MDR1), the multidrug transporter responsible for drug resistance of cancer cells. We have studied the effect of mutation I541F localized to the first nucleotide-binding domain, which is highly conserved between ABCB4 and ABCB1. Plasmids encoding the wild-type human ABCB4 or rat ABCB1-green fluorescing protein (GFP) construct, and corresponding I541F-mutants, were expressed in hepatocellular carcinoma, human (HepG2) and Madin-Darby canine kidney (MDCK) cells. Expression studies showed that ABCB4 was localized at the bile canalicular membrane in HepG2 cells and at the apical surface in MDCK cells, whereas the I541F mutant was intracellular. In MDCK cells, ABCB1-I541F also accumulated intracellularly in compartments, which were identified as the endoplasmic reticulum and cis-Golgi, and remained partially endoH-sensitive. After shifting cells to 27°C, ABCB1-I541F was expressed at the apical cell surface in a mature and active form. Similarly, ABCB4 was significantly trafficked to the membrane of bile canaliculi in HepG2 cells. Conclusion: Mutation I541F causes mislocalization of both ABCB4 and ABCB1. Intracellular retention of ABCB4-I541F can explain the disease in PFIC3 patients bearing this mutation. The observation that plasma membrane expression and activity can be rescued by low temperature opens perspectives to develop novel therapies for the treatment of PFIC3. (HEPATOLOGY 2009;49:1218-1227

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“…An N-terminal dileucine-based signal (AAASLLAP) is involved in directing NPP1 to the basolateral membrane of polarized MDCK cells [400] or to matrix vesicles of mineralizing cells [314]. NPP3 lacks the cytosolic dileucine motif and is apically targeted in the polarized MDCK and Caco-2 cells and in airway epithelia [315].…”

Section: General Molecular Propertiesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Characterization of a Di-leucine–based Signal in the Cytoplasmic Tail of the Nucleotide-pyrophosphatase NPP1 That Mediates Basolateral Targeting but not Endocytosis

Cited by 54 publications

References 59 publications

A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen

A Novel Cytoplasmic Tail MXXXL Motif Mediates the Internalization of Prostate-specific Membrane Antigen

A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature #

Cellular function and molecular structure of ecto-nucleotidases

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