Formin INF2 regulates MAL-mediated transport of Lck to the plasma membrane of human T lymphocytes
Expression of the src-family kinase lymphocyte-specific protein tyrosine kinase (Lck) at the plasma membrane is essential for it to fulfill its pivotal role in signal transduction in T lymphocytes. MAL, an integral membrane protein expressed in specific types of lymphoma, has been shown to play an i...
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| Veröffentlicht in: | Blood 2010-12, Vol.116 (26), p.5919-5929 |
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| creator | Andrés-Delgado, Laura Antón, Olga M. Madrid, Ricardo Byrne, Jennifer A. Alonso, Miguel A. |
| description | Expression of the src-family kinase lymphocyte-specific protein tyrosine kinase (Lck) at the plasma membrane is essential for it to fulfill its pivotal role in signal transduction in T lymphocytes. MAL, an integral membrane protein expressed in specific types of lymphoma, has been shown to play an important role in targeting Lck to the plasma membrane. Here we report that MAL interacts with Inverted Formin2 (INF2), a formin with the atypical property of promoting not only actin polymerization but also its depolymerization. In Jurkat T cells, INF2 colocalizes with MAL at the cell periphery and pericentriolar endosomes and along microtubules. Videomicroscopic analysis revealed that the MAL+ vesicles transporting Lck to the plasma membrane move along microtubule tracks. Knockdown of INF2 greatly reduced the formation of MAL+ transport vesicles and the levels of Lck at the plasma membrane and impaired formation of a normal immunologic synapse. The actin polymerization and depolymerization activities of INF2 were both required for efficient Lck targeting. Cdc42 and Rac1, which bind to INF2, regulate Lck transport in both Jurkat and primary human T cells. Thus, INF2 collaborates with MAL in the formation of specific carriers for targeting Lck to the plasma membrane in a process regulated by Cdc42 and Rac1. |
| doi_str_mv | 10.1182/blood-2010-08-300665 |
| format | Article |
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MAL, an integral membrane protein expressed in specific types of lymphoma, has been shown to play an important role in targeting Lck to the plasma membrane. Here we report that MAL interacts with Inverted Formin2 (INF2), a formin with the atypical property of promoting not only actin polymerization but also its depolymerization. In Jurkat T cells, INF2 colocalizes with MAL at the cell periphery and pericentriolar endosomes and along microtubules. Videomicroscopic analysis revealed that the MAL+ vesicles transporting Lck to the plasma membrane move along microtubule tracks. Knockdown of INF2 greatly reduced the formation of MAL+ transport vesicles and the levels of Lck at the plasma membrane and impaired formation of a normal immunologic synapse. The actin polymerization and depolymerization activities of INF2 were both required for efficient Lck targeting. Cdc42 and Rac1, which bind to INF2, regulate Lck transport in both Jurkat and primary human T cells. 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Thus, INF2 collaborates with MAL in the formation of specific carriers for targeting Lck to the plasma membrane in a process regulated by Cdc42 and Rac1.</description><subject>Actin</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>cdc42 GTP-Binding Protein - metabolism</subject><subject>Cell Membrane - metabolism</subject><subject>Cytoplasm - metabolism</subject><subject>Endosomes - metabolism</subject><subject>Formins</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Jurkat Cells</subject><subject>Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism</subject><subject>Medical sciences</subject><subject>Membrane Transport Proteins - metabolism</subject><subject>Microfilament Proteins - pharmacology</subject><subject>Myelin and Lymphocyte-Associated Proteolipid Proteins</subject><subject>Myelin Proteins - metabolism</subject><subject>Protein Transport</subject><subject>Proteolipids - metabolism</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>T-Lymphocytes - metabolism</subject><subject>Transport Vesicles - metabolism</subject><subject>Two-Hybrid System Techniques</subject><subject>Vesicular Transport Proteins - metabolism</subject><issn>0006-4971</issn><issn>1528-0020</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFP3DAQha2qVVlo_0GFfKngknbsOLFzqYQQC0hLe6Fny7Gdbkq8Tu0Eaf89s90Fbpys8Xwz8_QeIV8YfGNM8e_tEKMrODAoQBUlQF1X78iCVVwVABzekwXgZyEayY7Icc5_AZgoefWRHHFQinGQC2KWMYV-Q29_LjlN_s88mMlnenexKoJ3PRaOTsls8hjTRGNHV_aBTpFOa0_HweRgaPChRcLvuus5mA29p8M2jOtot7jrE_nQmSH7z4f3hPxeXt1f3hSrX9e3l3jHCglTwVG-cB2rO-nAWcctF1YaV9aigbo1THglnILKqlqZxvIGO9A10DrWys6UJ-Rsv3dM8d_s86RDn60fBpQW56wVZ6xRIBskz98kmahFBRJAIir2qE0x5-Q7PaY-mLTVDPQuBv0_Br2LQYPS-xhw7PRwYW7RxpehZ98R-HoATLZm6NA_2-dXrqwbxSVH7see8-jcY--Tzrb3G4vRJG8n7WL_tpInBamk4w</recordid><startdate>20101223</startdate><enddate>20101223</enddate><creator>Andrés-Delgado, Laura</creator><creator>Antón, Olga M.</creator><creator>Madrid, Ricardo</creator><creator>Byrne, Jennifer A.</creator><creator>Alonso, Miguel A.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20101223</creationdate><title>Formin INF2 regulates MAL-mediated transport of Lck to the plasma membrane of human T lymphocytes</title><author>Andrés-Delgado, Laura ; 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MAL, an integral membrane protein expressed in specific types of lymphoma, has been shown to play an important role in targeting Lck to the plasma membrane. Here we report that MAL interacts with Inverted Formin2 (INF2), a formin with the atypical property of promoting not only actin polymerization but also its depolymerization. In Jurkat T cells, INF2 colocalizes with MAL at the cell periphery and pericentriolar endosomes and along microtubules. Videomicroscopic analysis revealed that the MAL+ vesicles transporting Lck to the plasma membrane move along microtubule tracks. Knockdown of INF2 greatly reduced the formation of MAL+ transport vesicles and the levels of Lck at the plasma membrane and impaired formation of a normal immunologic synapse. The actin polymerization and depolymerization activities of INF2 were both required for efficient Lck targeting. Cdc42 and Rac1, which bind to INF2, regulate Lck transport in both Jurkat and primary human T cells. 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| subjects | Actin Biological and medical sciences Blotting, Western cdc42 GTP-Binding Protein - metabolism Cell Membrane - metabolism Cytoplasm - metabolism Endosomes - metabolism Formins Hematologic and hematopoietic diseases Humans Immunoprecipitation Jurkat Cells Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism Medical sciences Membrane Transport Proteins - metabolism Microfilament Proteins - pharmacology Myelin and Lymphocyte-Associated Proteolipid Proteins Myelin Proteins - metabolism Protein Transport Proteolipids - metabolism rac1 GTP-Binding Protein - metabolism T-Lymphocytes - metabolism Transport Vesicles - metabolism Two-Hybrid System Techniques Vesicular Transport Proteins - metabolism |
| title | Formin INF2 regulates MAL-mediated transport of Lck to the plasma membrane of human T lymphocytes |
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