Mechanism and function of Vav1 localisation in TCR signalling
The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) si...
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| Veröffentlicht in: | Journal of cell science 2012-11, Vol.125 (Pt 22), p.5302-5314 |
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| container_issue | Pt 22 |
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| container_title | Journal of cell science |
| container_volume | 125 |
| creator | Ksionda, Olga Saveliev, Alexander Köchl, Robert Rapley, Jonathan Faroudi, Mustapha Smith-Garvin, Jennifer E Wülfing, Christoph Rittinger, Katrin Carter, Tom Tybulewicz, Victor L J |
| description | The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) signalling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4(+) and CD8(+) T cells. Furthermore, we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3(B)) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3(B) domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signalling function in TCR-induced calcium flux. We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux. |
| doi_str_mv | 10.1242/jcs.105148 |
| format | Article |
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The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) signalling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4(+) and CD8(+) T cells. Furthermore, we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3(B)) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3(B) domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signalling function in TCR-induced calcium flux. We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux.</description><identifier>ISSN: 0021-9533</identifier><identifier>EISSN: 1477-9137</identifier><identifier>DOI: 10.1242/jcs.105148</identifier><identifier>PMID: 22956543</identifier><language>eng</language><publisher>England: The Company of Biologists</publisher><subject>Animals ; Calcium - metabolism ; CD4-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - metabolism ; Cells, Cultured ; Humans ; Immunological Synapses - metabolism ; Mice ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; Phosphorylation ; Protein Transport - immunology ; Proto-Oncogene Proteins c-vav - chemistry ; Proto-Oncogene Proteins c-vav - metabolism ; Receptors, Antigen, T-Cell - metabolism ; Signal Transduction - immunology ; src Homology Domains</subject><ispartof>Journal of cell science, 2012-11, Vol.125 (Pt 22), p.5302-5314</ispartof><rights>2012. 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We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux.</description><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cells, Cultured</subject><subject>Humans</subject><subject>Immunological Synapses - metabolism</subject><subject>Mice</subject><subject>Mutant Proteins - chemistry</subject><subject>Mutant Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Transport - immunology</subject><subject>Proto-Oncogene Proteins c-vav - chemistry</subject><subject>Proto-Oncogene Proteins c-vav - metabolism</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>Signal Transduction - immunology</subject><subject>src Homology Domains</subject><issn>0021-9533</issn><issn>1477-9137</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF1LwzAUhoMobk5v_AHSSxGq-U57oSDDL5gIMr0NaZZsGWkym3bgv7e6OfTqwHse3nN4ADhF8BJhiq-WOl0iyBAt9sAQUSHyEhGxD4YQYpSXjJABOEppCSEUuBSHYIBxyTijZAiun41eqOBSnakwy2wXdOtiyKLN3tUaZT5q5V1SP6EL2XT8miU3D8p7F-bH4MAqn8zJdo7A2_3ddPyYT14ensa3k1wTUbQ5gUpbxoRQgioiEIQzxgVmBaNcE0I4JLTSyFBUIStKVVHNVSkM1MJCYTkZgZtN76qrajPTJrSN8nLVuFo1nzIqJ_9vglvIeVxLwjgqegEjcL4taOJHZ1Ira5e08V4FE7skES4oLnhJcI9ebFDdxJQaY3dnEJTfvmXvW2589_DZ38d26K9g8gVCQnqu</recordid><startdate>20121115</startdate><enddate>20121115</enddate><creator>Ksionda, Olga</creator><creator>Saveliev, Alexander</creator><creator>Köchl, Robert</creator><creator>Rapley, Jonathan</creator><creator>Faroudi, Mustapha</creator><creator>Smith-Garvin, Jennifer E</creator><creator>Wülfing, Christoph</creator><creator>Rittinger, Katrin</creator><creator>Carter, Tom</creator><creator>Tybulewicz, Victor L J</creator><general>The Company of Biologists</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20121115</creationdate><title>Mechanism and function of Vav1 localisation in TCR signalling</title><author>Ksionda, Olga ; Saveliev, Alexander ; Köchl, Robert ; Rapley, Jonathan ; Faroudi, Mustapha ; Smith-Garvin, Jennifer E ; Wülfing, Christoph ; Rittinger, Katrin ; Carter, Tom ; Tybulewicz, Victor L J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-30acf5577a74a37100d567258546c3336034bc1e41b1f79ab4c6a97e0c7f07f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Cells, Cultured</topic><topic>Humans</topic><topic>Immunological Synapses - metabolism</topic><topic>Mice</topic><topic>Mutant Proteins - chemistry</topic><topic>Mutant Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Transport - immunology</topic><topic>Proto-Oncogene Proteins c-vav - chemistry</topic><topic>Proto-Oncogene Proteins c-vav - metabolism</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>Signal Transduction - immunology</topic><topic>src Homology Domains</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ksionda, Olga</creatorcontrib><creatorcontrib>Saveliev, Alexander</creatorcontrib><creatorcontrib>Köchl, Robert</creatorcontrib><creatorcontrib>Rapley, Jonathan</creatorcontrib><creatorcontrib>Faroudi, Mustapha</creatorcontrib><creatorcontrib>Smith-Garvin, Jennifer E</creatorcontrib><creatorcontrib>Wülfing, Christoph</creatorcontrib><creatorcontrib>Rittinger, Katrin</creatorcontrib><creatorcontrib>Carter, Tom</creatorcontrib><creatorcontrib>Tybulewicz, Victor L J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cell science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ksionda, Olga</au><au>Saveliev, Alexander</au><au>Köchl, Robert</au><au>Rapley, Jonathan</au><au>Faroudi, Mustapha</au><au>Smith-Garvin, Jennifer E</au><au>Wülfing, Christoph</au><au>Rittinger, Katrin</au><au>Carter, Tom</au><au>Tybulewicz, Victor L J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism and function of Vav1 localisation in TCR signalling</atitle><jtitle>Journal of cell science</jtitle><addtitle>J Cell Sci</addtitle><date>2012-11-15</date><risdate>2012</risdate><volume>125</volume><issue>Pt 22</issue><spage>5302</spage><epage>5314</epage><pages>5302-5314</pages><issn>0021-9533</issn><eissn>1477-9137</eissn><abstract>The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) signalling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4(+) and CD8(+) T cells. Furthermore, we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3(B)) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3(B) domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signalling function in TCR-induced calcium flux. 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| ispartof | Journal of cell science, 2012-11, Vol.125 (Pt 22), p.5302-5314 |
| issn | 0021-9533 1477-9137 |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Company of Biologists |
| subjects | Animals Calcium - metabolism CD4-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - metabolism Cells, Cultured Humans Immunological Synapses - metabolism Mice Mutant Proteins - chemistry Mutant Proteins - metabolism Phosphorylation Protein Transport - immunology Proto-Oncogene Proteins c-vav - chemistry Proto-Oncogene Proteins c-vav - metabolism Receptors, Antigen, T-Cell - metabolism Signal Transduction - immunology src Homology Domains |
| title | Mechanism and function of Vav1 localisation in TCR signalling |
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