Characterization of Syntenin, a Syndecan-binding PDZ Protein, as a Component of Cell Adhesion Sites and Microfilaments

Zimmermann, Pascale; Tomatis, Daniela; Rosas, Marcela; Grootjans, Johan; Leenaerts, Iris; Degeest, Gisèle; Reekmans, Gunter; Coomans, Christien; Gourichon, David

doi:10.1091/mbc.12.2.339

Cited by 165 publications

(185 citation statements)

References 35 publications

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“…The role of DEP-1 in cell confluence inhibition may be related to its interaction with components of the cell-cell adhesion complex, that is, b-catenin and plakoglobin (Palka et al, 2003), and in particular to the dephosphorylation of p120 catenin DEP-1-mediated (Holsinger et al, 2002). In addition, syntenin, an r-PTPZ-interacting protein , is able to bind proteins of the cell-cell adhesion complex (Zimmermann et al, 2001). Finally, the reintroduction of the r-PTPZ gene into malignant rat thyroid cells increased their adhesion to the substratum (Trapasso et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

et al. 2005

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The expression of the receptor protein tyrosine phosphatase r-PTPg is drastically reduced in rat and human malignant thyroid cells, whereas its restoration reverts the neoplastic phenotype of retrovirally transformed rat thyroid cells. Moreover, reduced levels and loss of heterozygosity of DEP-1, the human homolog of r-PTPg, have been found in many human neoplasias. Here, we report that the r-PTPg protein binds to c-Src in living cells and dephosphorylates the c-Src inhibitory tyrosine phosphorylation site (Tyr 529), thereby increasing c-Src tyrosine kinase activity in malignant rat thyroid cells stably transfected with r-PTPg. Tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin was enhanced in r-PTPg-expressing cells. This was associated with increased adhesion of malignant r-PTPg-transfected thyroid cells vs both untransfected cells and cells stably transfected with an inactive r-PTPg mutant. Treatment of rat thyroid cells with the c-Src inhibitor PP2 decreased cell adhesion to a higher extent in r-PTPg-transfected cells than in mock-transfected or stably transfected cells with the inactive r-PTPg mutant, indicating that r-PTPg regulates cell-substratum adhesion by activating c-Src. Interestingly, the extent of both c-Src dephosphorylation at Tyr 529, FAK and paxillin phosphorylation, and the increased cell adhesion were associated with the degree of r-PTPg expression.

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Section: Introductionmentioning

confidence: 99%

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

et al. 2005

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“…Synergistic interaction of two PDZ domains has also been observed in other proteins containing multiple PDZ domains, including the N-terminal PDZ tandem of PSD-95 (ref. 32), PDZ4 and PDZ5 of the glutamate receptorinteracting proteins 33 and the PDZ tandem of syntenin 34 .…”

Section: Discussionmentioning

confidence: 99%

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

Long

Feng

Wang

et al. 2005

Nat Struct Mol Biol

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Members of the X11/Mint family of multidomain adaptor proteins are composed of a divergent N terminus, a conserved PTB domain and a pair of C-terminal PDZ domains. Many proteins can interact with the PDZ tandem of X11 proteins, although the mechanism of such interactions is unclear. Here we show that the highly conserved C-terminal tail of X11a folds back and inserts into the target-binding groove of the first PDZ domain. The binding of this tail occludes the binding of other target peptides. This autoinhibited conformation of X11 requires that the two PDZ domains and the entire C-terminal tail be covalently connected to form an integral structural unit. The autoinhibited conformation of the X11 PDZ tandem provides a mechanistic explanation for the unique target-binding properties of the protein and hints at potential regulatory mechanisms for the X11-target interactions.The X11/Mint family of multidomain scaffold proteins comprises three members: X11a/Mint1, X11b/Mint2 and X11g/Mint3 (refs. 1-5). X11a/Mint1 and X11b/Mint2 are neuron-specific proteins, whereas X11g/Mint3 is ubiquitously expressed 2,6-9 . Except for their isoform-specific N-terminal sequences, all X11/Mint proteins contain a central PTB domain and two C-terminal PDZ domains arranged in tandem (Fig. 1a). The PTB domain binds to the C-terminal YENPTY motif of amyloid precursor protein (APP). This interaction prolongs the half-life of cellular APP, thereby slowing the production of amyloid-b peptide 3,10-13 . A growing number of proteins that bind to the PDZ domains of X11/Mint proteins have been identified, including presenilin 13,14 , calcium channels 15 , neurexin 5 and AMPA receptors 16 . Although not directly involved in binding APP, the PDZ tandem of X11/Mint proteins has an indispensable role in PTB domain-mediated APP stabilization 13,17 . Available experimental data indicate that the binding of target proteins to isolated PDZ domains is distinctly different from the binding of those targets to two PDZ domains connected in tandem 13,14 . Current understanding of the structural and biochemical properties of the X11 PDZ domains cannot explain their unique target-binding properties.X11/Mint proteins are also implicated in polarized trafficking of receptors and ion channels to plasma membranes [18][19][20] . In Caenorhabditis elegans, mutation of lin-10 (the only X11/Mint homolog in C. elegans) results in mislocalization of the epidermal growth factor receptor, LET-23, and causes a signaling-defective (vulvaless) phenotype 18,20 . The proper localization of LET-23 requires an evolutionary conserved complex of LIN-2, LIN-7 and LIN-10 (CASK, Mals and X11a in mammals) 21 . Mutation of lin-10 also disrupts postsynaptic targeting of glutamate receptor-1 in C. elegans neurons 19 . X11a/Mint1 has been implicated in the kinesin-mediated transport of NMDA receptors to synapses 22,23 and is preferentially expressed in inhibitory neurons 24 . Deletion of X11a/Mint1 in mice impairs GABAergic synaptic transmission 24 . That X11a/Mint1 knockout study, however...

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“…injections (50 g each) of a recombinant soluble form of CD6 (17) in CFA (first) and IFA (next) (Invitrogen Life Technologies). The mouse antisyntenin mAbs 4D12 and 4F6 and the rabbit polyclonal anti-syntenin antiserum have been reported elsewhere (33). The anti-hemagglutinin (HA) mAb HA.11 was from Babco, and the biotin-labeled anti-HA mAb was from Santa Cruz Biotechnology.…”

Section: Chemicals and Absmentioning

confidence: 99%

The Lymphocyte Receptor CD6 Interacts with Syntenin-1, a Scaffolding Protein Containing PDZ Domains

Gimferrer

Ibáñez

Farnós

et al. 2005

The Journal of Immunology

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CD6 is a type I membrane glycoprotein expressed on thymocytes, mature T and B1a lymphocytes, and CNS cells. CD6 binds to activated leukocyte cell adhesion molecule (CD166), and is considered as a costimulatory molecule involved in lymphocyte activation and thymocyte development. Accordingly, CD6 partially associates with the TCR/CD3 complex and colocalizes with it at the center of the mature immunological synapse (IS) on T lymphocytes. However, the signaling pathway used by CD6 is still mostly unknown. The yeast two-hybrid system has allowed us the identification of syntenin-1 as an interacting protein with the cytoplasmic tail of CD6. Syntenin-1 is a PDZ (postsynaptic density protein-95, postsynaptic discs large, and zona occludens-1) domain-containing protein, which functions as an adaptor protein able to bind cytoskeletal proteins and signal transduction effectors. Mutational analyses showed that certain amino acids of the most C-terminal sequence of CD6 (-YDDISAA) and the two postsynaptic density protein-95, postsynaptic discs large, and zona occludens-1 domains of syntenin-1 are relevant to the interaction. Further confirmation of the CD6-syntenin-1 interaction was obtained from pull-down and coimmunoprecipitation assays in mammalian cells. Image analyses also showed that syntenin-1 accumulates at CD6 caps and at the IS. Therefore, we propose that syntenin-1 may function as a scaffolding protein coupling CD6 and most likely other lymphocyte receptors to cytoskeleton and/or signaling effectors during IS maturation.

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Characterization of Syntenin, a Syndecan-binding PDZ Protein, as a Component of Cell Adhesion Sites and Microfilaments

Cited by 165 publications

References 35 publications

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

The rat tyrosine phosphatase η increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

The Lymphocyte Receptor CD6 Interacts with Syntenin-1, a Scaffolding Protein Containing PDZ Domains

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