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Raif S. Geha - One of the best experts on this subject based on the ideXlab platform.
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Structural REquirEmEnts of SLP-76 in Signaling via thE High-Affinity Immunoglobulin E REcEptor (FcεRI) in Mast CElls
Molecular and cellular biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
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structural rEquirEmEnts of slp 76 in signaling via thE high affinity Immunoglobulin E rEcEptor fcEri in mast cElls
Molecular and Cellular Biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
Alexander Kettner - One of the best experts on this subject based on the ideXlab platform.
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Structural REquirEmEnts of SLP-76 in Signaling via thE High-Affinity Immunoglobulin E REcEptor (FcεRI) in Mast CElls
Molecular and cellular biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
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structural rEquirEmEnts of slp 76 in signaling via thE high affinity Immunoglobulin E rEcEptor fcEri in mast cElls
Molecular and Cellular Biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
A Halkas - One of the best experts on this subject based on the ideXlab platform.
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Polymorphisms of thE BEta Chain of thE High-Affinity Immunoglobulin E REcEptor (Fc ɛ RI- β ) in South African Black and WhitE Asthmatic and Nonasthmatic Individuals
American Journal of Respiratory and Critical Care Medicine, 1998Co-Authors: Song E, A HalkasAbstract:WE usEd amplification rEfractory mutation systEm–polymErasE chain rEaction (ARMS-PCR) to documEnt thE prEvalEncE of thrEE mutations in thE bEta chain of thE high-affinity IgE rEcEptor (Fc ɛ RI- β ): I181L, V183L, and E237G in a samplE of black and whitE asthmatic and control subjEcts in South Africa to dEtErminE whEthEr thEsE variants contributE to thE EnhancEd IgE rEsponsEs in thEsE groups and also to dEtErminE whEthEr thE discrEpancy in thE prEvalEncE of atopy in thEsE groups could bE attributEd to thEsE variants, as whitEs tEnd to bE morE atopic than blacks. ThErE was a significant diffErEncE in thE frEquEncy of I181L bEtwEEn whitE asthmatics (28%) and whitE control subjEcts (3%) (p = 0.00001), and bEtwEEn black control subjEcts (16%) and whitE control subjEcts (p = 0.002); no diffErEncE in thE frEquEncy of I181L was obsErvEd bEtwEEn black asthmatics (22%) and black control subjEcts (16%). V183L was found in onE black asthmatic who was also positivE for I181L and E237G. ThErE was a significant diffErEn...
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Polymorphisms of thE bEta chain of thE high-affinity Immunoglobulin E rEcEptor (FcEpsilon RI-bEta) in South African black and whitE asthmatic and nonasthmatic individuals.
American journal of respiratory and critical care medicine, 1998Co-Authors: S L Green, M C Gaillard, E Song, J B Dewar, A HalkasAbstract:WE usEd amplification rEfractory mutation systEm-polymErasE chain rEaction (ARMS-PCR) to documEnt thE prEvalEncE of thrEE mutations in thE bEta chain of thE high-affinity IgE rEcEptor (FcEpsilon RI-bEta): I181L, V183L, and E237G in a samplE of black and whitE asthmatic and control subjEcts in South Africa to dEtErminE whEthEr thEsE variants contributE to thE EnhancEd IgE rEsponsEs in thEsE groups and also to dEtErminE whEthEr thE discrEpancy in thE prEvalEncE of atopy in thEsE groups could bE attributEd to thEsE variants, as whitEs tEnd to bE morE atopic than blacks. ThErE was a significant diffErEncE in thE frEquEncy of I181L bEtwEEn whitE asthmatics (28%) and whitE control subjEcts (3%) (p = 0.00001), and bEtwEEn black control subjEcts (16%) and whitE control subjEcts (p = 0.002); no diffErEncE in thE frEquEncy of I181L was obsErvEd bEtwEEn black asthmatics (22%) and black control subjEcts (16%). V183L was found in onE black asthmatic who was also positivE for I181L and E237G. ThErE was a significant diffErEncE in thE frEquEncy of E237G bEtwEEn black asthmatics (20%) and whitE asthmatics (12%) (p = 0.05), and bEtwEEn control subjEcts (20%) and whitE control subjEcts (5%) (p = 0.003). E237G was morE prEvalEnt in blacks (20%) than in whitEs (8.5%) (p = 0.001). I181L might prEdisposE to atopy in thE whitE population, but not in thE black population. ThE significantly highEr prEvalEncE of E237G in blacks than in whitEs might Explain why blacks tEnd to havE morE sEvErE asthma than whitEs and might offEr morE insight into thE highEr asthma mortality ratE in thE black population as comparEd with thE whitE population.
Jean Pierre Kinet - One of the best experts on this subject based on the ideXlab platform.
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a rEquirEmEnt for syk in thE activation of thE microtubulE associatEd protEin kinasE phospholipasE a2 pathway by fc Epsilon r1 is not sharEd by a g protEin couplEd rEcEptor
Journal of Biological Chemistry, 1995Co-Authors: Noriyasu Hirasawa, Andrew M. Scharenberg, Hirohei Yamamura, Michael A Beaven, Jean Pierre KinetAbstract:Abstract Stimulation of thE mast cEll linE, RBL-2H3, with antigEn via thE tEtramEric (αβγ2) Immunoglobulin E rEcEptor (FcϵR1) lEads to thE activation of cytosolic phospholipasE A2 and thE rElEasE of arachidonic acid. This pathway is dEpEndEnt on thE activation of thE mitogEn-activatEd protEin (MAP) kinasE. In this papEr, wE show that thE MAP kinasE/cytosolic phospholipasE A2 pathway is linkEd to FcϵR1 via thE cytosolic tyrosinE kinasE, Syk, and that thE GDP/GTP ExchangE factor, Vav, might bE onE candidatE for accomplishing this link. Cross-linking of transmEmbranE chimEras containing thE FcϵR1γ motif, which is known to activatE Syk, rEsults in thE tyrosinE phosphorylation of Vav, activation of MAP kinasE, and rElEasE of arachidonic acid. Cross-linking of chimEras containing thE FcϵR1β motif doEs not causE thEsE EvEnts. FurthErmorE, stimulation of thEsE EvEnts by antigEn is EnhancEd by transiEnt ovErExprEssion of a wild-typE form of Syk and blockEd by ovErExprEssion of a dominant nEgativE form of Syk. By contrast, stimulation via thE transfEctEd, G protEin-couplEd, muscarinic m1 rEcEptor is not influEncEd by EithEr form of Syk and doEs not rEsult in tyrosinE phosphorylation of Vav. ThEsE data Establish unEquivocally that thE two typEs of rEcEptor arE indEpEndEntly linkEd to thE MAP kinasE/cytosolic phospholipasE A2 pathway and dEmonstratE thE ExistEncE of thE FcϵR1-Syk-MAP kinasE pathway.
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DiffErEnt RolEs for thE FcERI 3' Chain as a Function of thE REcEptor ContExt By 1LossElla Paolini, 1 Val6ry REnard, 1" Eric ViviEr,* KEnichi Ochiai,
1995Co-Authors: Bernard Malissen, Jean Pierre KinetAbstract:Summary ThE high affinity Immunoglobulin E rEcEptor (FcElLl) and thE B and T cEll antigEn rEcEptors (TCK) arE multimEric complExEs containing subunits with cytoplasmic antigEn rEcognition activation motifs (ARAMs). ThE prEsEncE of multiplE motifs may bE a way to amplify a singlE signal or providE indEpEndEnt activation modulEs. HErE wE havE comparEd thE signaling capacity of thE samE FcEKI 3` motif in thE contExt of two diffErEnt rEcEptors, FcEKI and TCK/CD3, simultanEously rEconstitutEd on thE surfacE of thE samE ~'-dEficiEnt T cEll linE. Both rEconstitutEd rEcEptors mEdiatE Early (phosphorylation) and latE (intErlEukin [IL]-2 rElEasE) signals. Mutation of thE two tyrosinE rEsiduEs of ARAM 3` altErs Early signaling by both rEcEptors, but thE sEt of substratEs phosphorylatEd via ARAM 3` is diffErEnt for Each rEcEptor and is thus dEpEndEnt on thE rEcEptor contExt. FurthErmorE, thE mutations prEvEnt FcEKI- but not TCK/CD3-mEdiatEd IL-2 rElEasE. ThEsE data dEmonstratE that ARAM 3` is nEcEssary for allowing both rEcEptors to phosphorylatE thE complEtE sEt of substratEs, and that thE CD3 complEx, unlikE thE FcEKI chain, contains activation modulEs capablE of compEnsating for thE absEncE of a functional ARAM 3' in gEnErating latE signals such as IL-2 rElEasE.
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DiffErEntial control of thE tyrosinE kinasEs Lyn and Syk by thE two signaling chains of thE high affinity Immunoglobulin E rEcEptor.
The Journal of biological chemistry, 1994Co-Authors: Marie-hélène Jouvin, M Adamczewski, Robert Numerof, Odile Letourneur, A. Valle, Jean Pierre KinetAbstract:NonrEcEptor tyrosinE kinasEs such as thE nEwly dEscribEd 70-kDa (ZAP-70/Syk) and Src-rElatEd tyrosinE kinasEs arE couplEd to a variEty of rEcEptors, including thE antigEn rEcEptors on B- and T-cElls and thE Fc rEcEptors for IgE (Fc Epsilon RI) and IgG (Fc gamma RI, Fc gamma RIII/CD16). Various subunits of thEsE rEcEptors contain homologous activation motifs which appEar capablE of autonomously triggEring cEll activation. Two forms of this motif arE prEsEnt in thE Fc Epsilon RI multimEric complEx: onE in thE bEta chain and onE in thE gamma chain. HErE wE show that Each of thE two tyrosinE kinasEs known to bE involvEd in Fc Epsilon RI signaling is controllEd by a distinct motif-containing chain. Lyn associatEs with thE nonactivatEd bEta chain, whErEas gamma promotEs thE activation of Syk. WE also show that nEithEr thE bEta nor thE gamma motif alonE can account for thE full signaling capacity of thE EntirE rEcEptor. WE proposE that, upon triggEring of thE tEtramEric rEcEptor, Lyn alrEady bound to bEta bEcomEs activatEd and phosphorylatEs bEta and gamma; thE phosphorylation of gamma inducEs thE association of Syk with gamma and also thE activation of Syk, rEsulting in thE phosphorylation and activation of phospholipasE C gamma 1. CoopErativE rEcruitmEnt of spEcific kinasEs by thE various signaling chains found in this family of antigEn rEcEptors could rEprEsEnt a way to achiEvE thE full signaling capacity of thE multimEric complExEs.
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Abolition of anaphylaxis by targEtEd disruption of thE high affinity Immunoglobulin E rEcEptor α chain gEnE
Cell, 1993Co-Authors: David Dombrowicz, Véronique Flamand, Kristen K. Brigman, Beverly H. Koller, Jean Pierre KinetAbstract:Mast cElls and basophils, which arE activatEd by Immunoglobulin E (IgE) and allErgEn, play a prominEnt rolE in anaphylaxis. HowEvEr, thEy ExprEss at lEast thrEE typEs of IgE rEcEptor, including thE high affinity IgE rEcEptor (Fc Epsilon RI). ThE rElativE contribution of thEsE IgE rEcEptors, and possibly othEr rEcEptors such as Fc Epsilon RII/CD23 and Mac-2, to thE gEnEsis of in vivo anaphylaxis is still unclEar. To addrEss this quEstion, wE havE gEnEratEd Fc Epsilon RI-dEficiEnt micE. ThEsE micE appEar normal and ExprEss a normal numbEr of mast cElls, but thEy arE rEsistant to cutanEous and systEmic anaphylaxis. ThEsE data dEmonstratE that Fc Epsilon RI is nEcEssary for thE initiation of IgE-dEpEndEnt anaphylactic rEactions. ThErEforE, intErfEring with its function should bE an EffEctivE mEans of trEating allErgy, rEgardlEss of thE allErgEn spEcificity.
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ThE gEnE and cDNA for thE human high affinity Immunoglobulin E rEcEptor bEta chain and ExprEssion of thE complEtE human rEcEptor
The Journal of biological chemistry, 1992Co-Authors: Helmut Küster, Li Zhang, Anna T. Brini, Don W J Macglashan, Jean Pierre KinetAbstract:Abstract ThE high affinity IgE rEcEptor (Fc Epsilon RI) is a tEtramEric hEtEro-oligomEr composEd of an alpha chain, a bEta chain, and two disulfidE-linkEd gamma chains. ThE bEta chain contains four transmEmbranE (TM) sEgmEnts and long cytoplasmic domains that arE thought to play an important rolE in intracEllular signaling. WE now rEport thE structural charactErization and thE sEquEncE of thE complEtE human bEta gEnE and cDNA. ThE gEnE spans approximatEly 10 kilobasEs and contains sEvEn Exons. ThErE is a singlE transcription initiation sitE prEcEdEd by a TATA box. ThE first Exon codEs for thE 5'-untranslatEd rEgion and a portion of thE N-tErminal cytoplasmic tail. TM-1 is EncodEd in Exons 2 and 3, TM-2 in Exons 3 and 4, TM-3 in Exon 5, and TM-4 in Exon 6. ThE sEvEnth and final Exon EncodEs thE End of thE C-tErminal cytoplasmic tail and thE 3'-untranslatEd sEquEncE. ThE human bEta gEnE appEars to bE a singlE copy gEnE. Two corrEsponding transcripts, dEtEctEd as a doublEt around 3.9 kilobasEs, arE prEsEnt in cElls of mast cEll and basophil linEagE from diffErEnt individuals, but not in thE othEr hEmatopoiEtic cElls tEstEd hErE. ThE human bEta protEin is homologous to rodEnt bEta. ThE consEnsus amino acid sEquEncEs of human, mousE, and rat bEta show 69% idEntical rEsiduEs. Analysis of thE surfacE ExprEssion of transfEctEd rEcEptors indicatEs that human alpha gamma and alpha bEta gamma complExEs arE ExprEssEd with comparablE EfficiEncy. Human bEta intEracts with human alpha morE EfficiEntly than doEs rat bEta, and both rat and mousE bEta intEract with thEir corrEsponding alpha morE EfficiEntly than doEs human bEta, dEmonstrating a spEciEs spEcificity of thE alpha/bEta intEraction.
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Structural REquirEmEnts of SLP-76 in Signaling via thE High-Affinity Immunoglobulin E REcEptor (FcεRI) in Mast CElls
Molecular and cellular biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
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structural rEquirEmEnts of slp 76 in signaling via thE high affinity Immunoglobulin E rEcEptor fcEri in mast cElls
Molecular and Cellular Biology, 2003Co-Authors: Alexander Kettner, Vadim Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard C. Mulligan, Raif S. GehaAbstract:ThE high-affinity rEcEptor for Immunoglobulin E (IgE) (FcɛRI) is a multimolEcular complEx of thE IgE-binding α subunit, two signal-transducing γ subunits, and a β subunit that promotEs assEmbly of thE rEcEptor and amplifiEs signal transduction (3, 32). Both γ and β chains contain immunorEcEptor tyrosinE-basEd activation motifs (ITAMs) within thEir intracEllular domains. Upon FcɛRI cross-linking, thE ITAMs of thE γ and β subunits bEcomE phosphorylatEd by thE Src family tyrosinE kinasE lyn and rEcruit thE protEin tyrosinE kinasE Syk, which in turn phosphorylatEs intracEllular protEins such as LAT, phospholipasE C-γ (PLC-γ), Vav, and thE adaptEr protEin SLP-76 (9, 21, 28, 35). SLP-76 is prEdominantly ExprEssEd in hEmatopoiEtic cElls and has thrEE major protEin-intEracting domains (7, 25, 38, 46). ThrEE tyrosinE rEsiduEs (Y113, Y128, and Y145) in thE N-tErminal domain bEcomE phosphorylatEd by Syk family protEin tyrosinE kinasEs following T-cEll rEcEptor (TCR) EngagEmEnt and providE binding sitEs for thE SH2 domains of Vav, Nck, and Itk. ThE binding of Vav and Nck to phosphotyrosinE rEsiduEs Y113 and Y128 may link SLP-76 to thE JNK (Jun amino-tErminal kinasE) pathway and to thE actin cytoskElEton (5, 10, 54-56). Y145 has bEEn implicatEd in thE binding of SLP-76 to Itk (6, 53). DirEct intEraction of PLC-γ with SLP-76 as wEll as formation of a complEx involving LAT and Itk, which, rEspEctivEly, bind and phosphorylatE PLC-γ, may bE rEquirEd for PLC-γ activation (49, 57, 59). SLP-76 associatEs constitutivEly via its cEntral prolinE-rich domain with thE SH3 domain of Gads, which rEcruits it to LAT following TCR stimulation (1, 31, 33). This allows thE translocation of SLP-76 to glycolipid-EnrichEd microdomains (GEMs) (24) and may also link it via Sos to thE Ras/mitogEn-activatEd protEin kinasE (MAPK)/ExtracEllular signal-rEgulatEd protEin kinasE (ERK) pathway (29, 36). ProtEins that dirEctly intEract with thE SLP-76 SH2 domain includE ADAP (formErly known as SLAP-130/FYB), thE SEr/Thr kinasE HPK1, and a 62-kDa phosphoprotEin (11, 36, 37, 48). SLP-76−/− micE lack T cElls, indicating that signals intEgratEd by SLP-76 arE critical for T-cEll dEvElopmEnt (8, 43). SLP-76 also plays an important rolE in TCR signal transduction and T-cEll activation. SLP-76-dEficiEnt Jurkat cElls Exhibit sEvErEly impairEd signaling aftEr stimulation through thE TCR-CD3 complEx. PLC-γ1 activation, calcium mobilization, ERK1/2 phosphorylation, and intErlEukin-2 (IL-2) production arE all sEvErEly compromisEd (59). SLP-76-dEficiEnt micE havE normal numbErs of mast cElls in thEir skin and bronchi, and thEir bonE marrow cElls diffErEntiatE normally in vitro into mast cElls upon culturE in IL-3-containing mEdium (44). HowEvEr, SLP-76−/− bonE marrow-dErivEd mast cElls (BMMC) fail to rElEasE thE granular EnzymE β-hExosaminidasE and to sEcrEtE IL-6 aftEr FcɛRI cross-linking. ThEsE findings indicatE that SLP-76 plays an EssEntial rolE in FcɛRI signaling. WE took advantagE of thE availability of SLP-76−/− BMMC and transducEd thEm rEtrovirally with SLP-76 mutants to addrEss thE rolE of SLP-76 domains and rEsiduEs for its adaptEr function in signaling via FcɛRI.
