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Jeanpaul Borg - One of the best experts on this subject based on the ideXlab platform.
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the erbb2 her2 receptor differentially interacts with erbin and pick1 psd 95 dlg zo 1 Domain proteins
Journal of Biological Chemistry, 2001Co-Authors: Fanny Jaulinbastard, Sylvie Marchetto, Daniel Birnbaum, Hiroko Saito, Andre Le Bivic, Vincent Ollendorff, Jeanpaul BorgAbstract:Abstract Identification of protein complexes associated with the ERBB2/HER2 receptor may help unravel the mechanisms of its activation and regulation in normal and pathological situations. Interactions between ERBB2/HER2 and Src homology 2 or phosphotyrosine binding Domain signaling proteins have been extensively studied. We have identified ERBIN and PICK1 as new binding partners for ERBB2/HER2 that associate with its carboxyl-terminal sequence through a PDZ (PSD-95/DLG/ZO-1) Domain. This peptide sequence acts as a dominant retention or targeting basolateral signal for receptors in epithelial cells. ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whose function is crucial in non vertebrates for epithelial homeostasis. Whereas ERBIN appears to locate ERBB2/HER2 to the basolateral epithelium, PICK1 is thought to be involved in the clustering of receptors. We show here that ERBIN and PICK1 bind to ERBB2/HER2 with different mechanisms, and we propose that these interactions are regulated in cells. Since ERBIN and PICK1 tend to oligomerize, further complexity of protein networks may participate in ERBB2/HER2 functions and specificity.
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sequence specific recognition of the internalization motif of the alzheimer s amyloid precursor protein by the x11 ptb Domain
The EMBO Journal, 1997Co-Authors: Zhongtao Zhang, Joseph Schlessinger, Jeanpaul Borg, Chihon Lee, Valsan Mandiyan, Benjamin Margolis, John KuriyanAbstract:The crystal structure of the phosphotyrosine‐binding Domain (PTB) of the X11 protein has been determined, in complex with unphosphorylated peptides corresponding to a region of β‐amyloid precursor protein (βAPP) that is required for receptor internalization. The mode of binding to X11 of the unphosphorylated peptides, which contain an NPxY motif, resembles that of phosphorylated peptides bound to the Shc and IRS‐1 PTB Domains. Eight peptide residues make specific contacts with the X11 PTB Domain, and they collectively achieve high affinity ( K D = 0.32 μM) and specificity. These results suggest that, in contrast to the SH2 Domains, the PTB Domains are primarily peptide‐binding Domains that have, in some cases, acquired specificity for phosphorylated tyrosines.
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the role of the shc phosphotyrosine interaction phosphotyrosine binding Domain and tyrosine phosphorylation sites in polyoma middle t antigen mediated cell transformation
Journal of Biological Chemistry, 1997Co-Authors: Pamela Blaikie, Emmanuel Fournier, Daniel Birnbaum, Jeanpaul Borg, Stephen M Dilworth, Benjamin MargolisAbstract:Abstract The phosphotyrosineinteraction (PI)/phosphotyrosinebinding (PTB) Domain of Shc binds specific tyrosine-phosphorylated motifs found on activated growth factor receptors and proteins such as polyoma virus middle T antigen (MT). Phenylalanine 198 (Phe198) has been identified as a crucial residue involved in the interaction of the Shc PI/PTB with phosphopeptides. In NIH 3T3 cells expressing MT, p52 Shc carrying the F198V mutation is weakly phosphorylated and does not bind MT or Grb2. Overexpression of the PI/PTB Domain alone as Shc amino acids 1–238 acted in a dominant interfering fashion blocking MT-induced transformation. However, expression of a slightly longer construct, Shc 1–260, which encompasses Tyr239/Tyr240, a novel Shc tyrosine phosphorylation site, did not block transformation. This was found to be due to the ability of Shc 1–260 to become tyrosine-phosphorylated and bind Grb2. Furthermore, full-length Shc in which Tyr239/Tyr240 had been mutated to phenylalanine did not become tyrosine-phosphorylated or bind Grb2 but did inhibit colony formation in soft agar. Conversely, p52 Shc carrying a mutation in the other tyrosine phosphorylation site, Tyr317, became heavily tyrosine-phosphorylated, bound Grb2, and gave rise to colonies in soft agar.
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interaction with the phosphotyrosine binding Domain phosphotyrosine interacting Domain of shc is required for the transforming activity of the flt4 vegfr3 receptor tyrosine kinase
Journal of Biological Chemistry, 1996Co-Authors: Emmanuel Fournier, Olivier Rosnet, Sylvie Marchetto, Christoph W Turck, Robert Rottapel, Pier Giuseppe Pelicci, Daniel Birnbaum, Jeanpaul BorgAbstract:The FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which belongs to the family of receptors for vascular endothelial growth factor. As the result of an alternative processing of primary mRNA transcripts, the long isoform differs from the short isoform by an additional stretch of 65 amino acid residues located at the C terminus and containing three tyrosine residues, Tyr1333, Tyr1337, and Tyr1363. Only the long isoform is endowed with a transforming capacity in fibroblasts. We show that this activity is related to the capacity of the tyrosine 1337-containing sequence to interact with the phosphotyrosine binding Domain of the SHC protein. This demonstrates that a functional property of this newly described Domain includes relay of mitogenic signals. In addition, it shows that the same receptor can mediate different functions through the optional binding of the phosphotyrosine binding Domain and that the alternative use of this Domain is sufficient to direct the signal toward different pathways.
Kodimangalam S. Ravichandran - One of the best experts on this subject based on the ideXlab platform.
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interaction of ced 6 gulp an adapter protein involved in engulfment of apoptotic cells with ced 1 and cd91 low density lipoprotein receptor related protein lrp
Journal of Biological Chemistry, 2002Co-Authors: Kumiko Nakadatsukui, Annie Tosellotrampont, Peter M Henson, Kodimangalam S. RavichandranAbstract:The prompt clearance of cells undergoing apoptosis is critical during embryonic development, normal tissue turnover, as well as inflammation and autoimmunity. The molecular details of the engulfment of apoptotic cells are not fully understood. ced-6 and its human homologue gulp, encode an adapter protein, whose function in engulfment is highly evolutionarily conserved; however, the upstream and downstream components of CED-6 mediated signaling are not known. Recently, ced-1 has been shown to encode a transmembrane protein on phagocytic cells, with two functional sequence motifs in its cytoplasmic tail that are important for engulfment. In this study, using a combination of biochemical approaches and yeast two-hybrid analysis, we present evidence for a physical interaction between GULP/CED-6 and one of the two motifs (NP XY motif) in the cytoplasmic tail of CED-1. The phosphotyrosine binding Domain of GULP was necessary and sufficient for this interaction. Since the precise mammalian homologue of CED-1 is not known, we undertook a database search for human proteins that contain the motifs shown to be important for CED-1 function and identified CD91/LRP (low density lipoprotein receptor-related protein) as one candidate. Interestingly, recent studies have also identified CD91/LRP as a receptor involved in the phagocytosis of apoptotic cells in mammals. The GULP phosphotyrosine binding Domain was able to specifically interact with one specific NP XY motif in the CD91 cytoplasmic tail. During these studies we have also identified the mouse GULP sequence. These studies suggest a physical link between CED-1 or CD91/LRP and the adapter protein CED-6/GULP during engulfment of apoptotic cells and further elucidate the pathway suggested by the genetic studies.
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shc interaction with src homology 2 Domain containing inositol phosphatase ship in vivo requires the shc phosphotyrosine binding Domain and two specific phosphotyrosines on ship
Journal of Biological Chemistry, 1997Co-Authors: Thomas D Lamkin, Scott F Walk, Ling Liu, Jacqueline E Damen, Gerald Krystal, Kodimangalam S. RavichandranAbstract:Abstract The adapter protein Shc has been implicated in mitogenic signaling via growth factor receptors, cytokine receptors, and antigen receptors on lymphocytes. Besides the well characterized interaction of Shc with molecules involved in Ras activation, Shc also associates with a 145-kDa tyrosine-phosphorylated protein upon triggering via antigen receptors and many cytokine receptors. This 145-kDa protein has been recently identified as an SH2 Domain containing 5′-inositol phosphatase (SHIP) and has been implicated in the regulation of growth and differentiation in hematopoietic cells. In this report, we have addressed the molecular details of the interaction between Shc and SHIPin vivo. During T cell receptor signaling, tyrosine phosphorylation of SHIP and its association with Shc occurred only upon activation. We demonstrate that the phosphotyrosine binding Domain of Shc is necessary and sufficient for its association with tyrosine-phosphorylated SHIP. Through site-directed mutagenesis, we have identified two tyrosines on SHIP, Tyr-917, and Tyr-1020, as the principal contact sites for the Shc-phosphotyrosine binding Domain. Our data also suggest a role for the tyrosine kinase Lck in phosphorylation of SHIP. We also show that the SH2 Domain of SHIP is dispensable for the Shc-SHIP interaction in vivo. These data have implications for the localization of the Shc·SHIP complex and regulation of SHIP function during T cell receptor signaling.
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Structure and ligand recognition of the phosphotyrosine binding Domain of Shc.
Nature, 1995Co-Authors: Ming-ming Zhou, Kodimangalam S. Ravichandran, Warren S. Wade, John E. Harlan, Edward T Olejniczak, Robert P Meadows, Andrew M. Petros, Michael Sattler, Steven J. Burakoff, Stephen W FesikAbstract:The nuclear magnetic resonance structure of the phosphotyrosine binding (PTB) Domain of She complexed to a phosphopeptide reveals an alternative means of recognizing tryosine-phosphorylated proteins. Unlike in SH2 Domains, the phosphopeptide forms an antiparallel β-strand with a β-sheet of the protein, interacts with a hydrophobic pocket through the (pY–5) residue, and adopts a β-turn. The PTB Domain is structurally similar to pleckstrin homology Domains (a β-sandwich capped by an α-helix) and binds to acidic phospholipids, suggesting a possible role in membrane localization.
Tony Pawson - One of the best experts on this subject based on the ideXlab platform.
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src homology 2 Domain containing protein 5 sh2d5 binds the breakpoint cluster region protein bcr and regulates levels of rac1 gtp
Journal of Biological Chemistry, 2014Co-Authors: Elizabeth J Gray, Evangelia Petsalaki, Andrew D James, Richard D Bagshaw, Melissa M Stacey, Oliver Rocks, Anneclaude Gingras, Tony PawsonAbstract:SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal Phosphotyrosine-Binding Domain and a C-terminal Src homology 2 (SH2) Domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition Domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 Domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with breakpoint cluster region protein, a RacGAP that is also highly expressed in brain. This interaction occurred between the Phosphotyrosine-Binding Domain of SH2D5 and an NxxF motif located within the N-terminal region of the breakpoint cluster region. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein.
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the discoidin Domain receptor tyrosine kinases are activated by collagen
Molecular Cell, 1997Co-Authors: Wolfgang Vogel, Gerrald D Gish, Tony PawsonAbstract:Abstract Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular Domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation. Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding Domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. These results suggest that the discoidin-related DDR tyrosine kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.
Hamid Band - One of the best experts on this subject based on the ideXlab platform.
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cbl mediated negative regulation of the syk tyrosine kinase a critical role for cbl phosphotyrosine binding Domain binding to syk phosphotyrosine 323
Journal of Biological Chemistry, 1998Co-Authors: Mark L Lupher, Navin Rao, Nancy L Lill, Christopher E Andoniou, Sachiko Miyake, Edward A Clark, Brian J Druker, Hamid BandAbstract:Abstract The proto-oncogene product Cbl has emerged as a potential negative regulator of the Syk tyrosine kinase; however, the nature of physical interactions between Cbl and Syk that are critical for this negative regulation remains unclear. Here we show that the Phosphotyrosine-Binding (PTB) Domain within the N-terminal transforming region of Cbl (Cbl-N) binds to phosphorylated Tyr323in the linker region between the Src homology 2 and kinase Domains of Syk, confirming recent results by another laboratory using the yeast two-hybrid approach (Deckert, M., Elly, C., Altman, A., and Liu, Y. C. (1998) J. Biol. Chem. 273, 8867–8874). A PTB Domain-inactivating point mutation (G306E), corresponding to a loss-of-function mutation in the Caenorhabditis elegans Cbl homologue SLI-1, severely compromised Cbl-N/Syk binding in vitro and Cbl/Syk association in transfected COS-7 cells. Using heterologous expression in COS-7 cells, we investigated the role of Cbl PTB Domain binding to Syk Tyr323 in the negative regulation of Syk. Co-expression of Cbl with Syk in COS-7 cells led to a dose-dependent decrease in the autophosphorylated pool of Syk and in phosphorylation of an in vivo substrate, CD8-ζ. Unexpectedly, these effects were largely due to the loss of Syk protein. Both the decrease in Syk and CD8-ζ phosphorylation and reduction in Syk protein levels were blocked by either G306E mutation in Cbl or by Y323F mutation in Syk. These results demonstrate a critical role for the Cbl PTB Domain in the recruitment of Cbl to Syk and in Cbl-mediated negative regulation of Syk.
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the cbl phosphotyrosine binding Domain selects a d n d xpy motif and binds to the tyr292negative regulatory phosphorylation site of zap 70
Journal of Biological Chemistry, 1997Co-Authors: Mark L Lupher, Zhou Songyang, Steven E Shoelson, Lewis C Cantley, Hamid BandAbstract:The Cbl protooncogene product has emerged as a novel negative regulator of receptor and non-receptor tyrosine kinases through currently undefined mechanisms. Therefore, determining how Cbl physically interacts with tyrosine kinases is of substantial interest. We recently identified a phosphotyrosine binding (PTB) Domain residing within the N-terminal transforming region of Cbl (Cbl-N), which mediated direct binding to ZAP-70 tyrosine kinase. Here, we have screened a degenerate phosphopeptide library and show that the Cbl-PTB Domain selects a D(N/D)XpY motif, reminiscent of but distinct from the NPXpY motif recognized by the PTB Domains of Shc and IRS-1/2. A phosphopeptide predicted by this motif and corresponding to the in vivo negative regulatory phosphorylation site of ZAP-70 (Tyr(P)292) specifically inhibited binding of ZAP-70 to Cbl-N. A ZAP-70/Y292F mutant failed to bind to Cbl-N, whereas a D290A mutant resulted in a 64% decrease in binding, confirming the importance of the Tyr(P) and Y-2 residues in Cbl-PTB Domain recognition. Finally the ZAP-70/Y292F mutant also failed to associate with Cbl-N or full-length Cbl in vivo. These results identify a potential Cbl-PTB Domain-dependent role for Cbl in the negative regulation of ZAP-70 and predict potential Cbl-PTB Domain binding sites on other protein tyrosine kinases known to interact with Cbl.
Mark L Lupher - One of the best experts on this subject based on the ideXlab platform.
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cbl mediated negative regulation of the syk tyrosine kinase a critical role for cbl phosphotyrosine binding Domain binding to syk phosphotyrosine 323
Journal of Biological Chemistry, 1998Co-Authors: Mark L Lupher, Navin Rao, Nancy L Lill, Christopher E Andoniou, Sachiko Miyake, Edward A Clark, Brian J Druker, Hamid BandAbstract:Abstract The proto-oncogene product Cbl has emerged as a potential negative regulator of the Syk tyrosine kinase; however, the nature of physical interactions between Cbl and Syk that are critical for this negative regulation remains unclear. Here we show that the Phosphotyrosine-Binding (PTB) Domain within the N-terminal transforming region of Cbl (Cbl-N) binds to phosphorylated Tyr323in the linker region between the Src homology 2 and kinase Domains of Syk, confirming recent results by another laboratory using the yeast two-hybrid approach (Deckert, M., Elly, C., Altman, A., and Liu, Y. C. (1998) J. Biol. Chem. 273, 8867–8874). A PTB Domain-inactivating point mutation (G306E), corresponding to a loss-of-function mutation in the Caenorhabditis elegans Cbl homologue SLI-1, severely compromised Cbl-N/Syk binding in vitro and Cbl/Syk association in transfected COS-7 cells. Using heterologous expression in COS-7 cells, we investigated the role of Cbl PTB Domain binding to Syk Tyr323 in the negative regulation of Syk. Co-expression of Cbl with Syk in COS-7 cells led to a dose-dependent decrease in the autophosphorylated pool of Syk and in phosphorylation of an in vivo substrate, CD8-ζ. Unexpectedly, these effects were largely due to the loss of Syk protein. Both the decrease in Syk and CD8-ζ phosphorylation and reduction in Syk protein levels were blocked by either G306E mutation in Cbl or by Y323F mutation in Syk. These results demonstrate a critical role for the Cbl PTB Domain in the recruitment of Cbl to Syk and in Cbl-mediated negative regulation of Syk.
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the cbl phosphotyrosine binding Domain selects a d n d xpy motif and binds to the tyr292negative regulatory phosphorylation site of zap 70
Journal of Biological Chemistry, 1997Co-Authors: Mark L Lupher, Zhou Songyang, Steven E Shoelson, Lewis C Cantley, Hamid BandAbstract:The Cbl protooncogene product has emerged as a novel negative regulator of receptor and non-receptor tyrosine kinases through currently undefined mechanisms. Therefore, determining how Cbl physically interacts with tyrosine kinases is of substantial interest. We recently identified a phosphotyrosine binding (PTB) Domain residing within the N-terminal transforming region of Cbl (Cbl-N), which mediated direct binding to ZAP-70 tyrosine kinase. Here, we have screened a degenerate phosphopeptide library and show that the Cbl-PTB Domain selects a D(N/D)XpY motif, reminiscent of but distinct from the NPXpY motif recognized by the PTB Domains of Shc and IRS-1/2. A phosphopeptide predicted by this motif and corresponding to the in vivo negative regulatory phosphorylation site of ZAP-70 (Tyr(P)292) specifically inhibited binding of ZAP-70 to Cbl-N. A ZAP-70/Y292F mutant failed to bind to Cbl-N, whereas a D290A mutant resulted in a 64% decrease in binding, confirming the importance of the Tyr(P) and Y-2 residues in Cbl-PTB Domain recognition. Finally the ZAP-70/Y292F mutant also failed to associate with Cbl-N or full-length Cbl in vivo. These results identify a potential Cbl-PTB Domain-dependent role for Cbl in the negative regulation of ZAP-70 and predict potential Cbl-PTB Domain binding sites on other protein tyrosine kinases known to interact with Cbl.