Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation
The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mec...
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| Veröffentlicht in: | Science signaling 2009-02, Vol.2 (59), p.ra7-ra7 |
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| container_title | Science signaling |
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| creator | Inoue, Akane Setoguchi, Kiyoko Matsubara, Yosuke Okada, Kumiko Sato, Nozomi Iwakura, Yoichiro Higuchi, Osamu Yamanashi, Yuji |
| description | The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural agrin. |
| doi_str_mv | 10.1126/scisignal.2000113 |
| format | Article |
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We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. 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We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural agrin.</description><subject>Agrin</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Enzyme Activation - genetics</subject><subject>Enzyme Activation - physiology</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>In Situ Hybridization</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Muscle Proteins - genetics</subject><subject>Muscle Proteins - metabolism</subject><subject>Neuromuscular Junction - metabolism</subject><subject>Neuromuscular Junction - physiology</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><issn>1945-0877</issn><issn>1937-9145</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtOwzAQRS0EolD4ADYoK3YpHtux4yUqT1HEAlhHE3dCQ_PCTpD696RqBau5Gp17F4exC-AzAKGvgytD-dlgNROccwB5wE7AShNbUMnhNqsk5qkxE3YawhfnGoSwx2wCViglQJywxW27jk2Eri9_sKcQ9SuK6iG4iiJPjrq-9dG6bDBQ9DK8PUfYLKOwwm5Ew6bBbvwXra-xL9vmjB0VWAU6398p-7i_e58_xovXh6f5zSJ20uo-NtxJEonSiU3BGCi4RJUikNaQ8yK3lOSJIyU5oEkJk1zqggiBCylyxeWUXe12O99-DxT6rC6Do6rChtohZFpbraSyIwg70Pk2BE9F1vmyRr_JgGdbhdmfwmyvcOxc7seHvKblf2PvTP4CRjRucw</recordid><startdate>20090224</startdate><enddate>20090224</enddate><creator>Inoue, Akane</creator><creator>Setoguchi, Kiyoko</creator><creator>Matsubara, Yosuke</creator><creator>Okada, Kumiko</creator><creator>Sato, Nozomi</creator><creator>Iwakura, Yoichiro</creator><creator>Higuchi, Osamu</creator><creator>Yamanashi, Yuji</creator><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></search><sort><creationdate>20090224</creationdate><title>Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation</title><author>Inoue, Akane ; Setoguchi, Kiyoko ; Matsubara, Yosuke ; Okada, Kumiko ; Sato, Nozomi ; Iwakura, Yoichiro ; Higuchi, Osamu ; Yamanashi, Yuji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-70c3e25465981771f03a48a1e661b0fb9e5b5ce4301a78ea5b36feea10232b403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Agrin</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Enzyme Activation - genetics</topic><topic>Enzyme Activation - physiology</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>In Situ Hybridization</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Muscle Proteins - genetics</topic><topic>Muscle Proteins - metabolism</topic><topic>Neuromuscular Junction - metabolism</topic><topic>Neuromuscular Junction - physiology</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inoue, Akane</creatorcontrib><creatorcontrib>Setoguchi, Kiyoko</creatorcontrib><creatorcontrib>Matsubara, Yosuke</creatorcontrib><creatorcontrib>Okada, Kumiko</creatorcontrib><creatorcontrib>Sato, Nozomi</creatorcontrib><creatorcontrib>Iwakura, Yoichiro</creatorcontrib><creatorcontrib>Higuchi, Osamu</creatorcontrib><creatorcontrib>Yamanashi, Yuji</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><jtitle>Science signaling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inoue, Akane</au><au>Setoguchi, Kiyoko</au><au>Matsubara, Yosuke</au><au>Okada, Kumiko</au><au>Sato, Nozomi</au><au>Iwakura, Yoichiro</au><au>Higuchi, Osamu</au><au>Yamanashi, Yuji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation</atitle><jtitle>Science signaling</jtitle><addtitle>Sci Signal</addtitle><date>2009-02-24</date><risdate>2009</risdate><volume>2</volume><issue>59</issue><spage>ra7</spage><epage>ra7</epage><pages>ra7-ra7</pages><issn>1945-0877</issn><eissn>1937-9145</eissn><abstract>The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural agrin.</abstract><cop>United States</cop><pmid>19244212</pmid><doi>10.1126/scisignal.2000113</doi></addata></record> |
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| source | MEDLINE; American Association for the Advancement of Science |
| subjects | Agrin Animals Cell Line Enzyme Activation - genetics Enzyme Activation - physiology Green Fluorescent Proteins - metabolism Humans Immunoblotting Immunoprecipitation In Situ Hybridization Mice Mice, Transgenic Muscle Proteins - genetics Muscle Proteins - metabolism Neuromuscular Junction - metabolism Neuromuscular Junction - physiology Receptor Protein-Tyrosine Kinases - metabolism |
| title | Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation |
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