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The Neurofibromatosis Type 1 Gene Product Neurofibromin Enhances Cell Motility by Regulating Actin Filament Dynamics via the Rho-ROCK-LIMK2-Cofilin Pathway
Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell...
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| Published in: | The Journal of biological chemistry 2005-11, Vol.280 (47), p.39524-39533 |
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| container_issue | 47 |
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| creator | Ozawa, Tatsuya Araki, Norie Yunoue, Shunji Tokuo, Hiroshi Feng, Liping Patrakitkomjorn, Siriporn Hara, Toshihiro Ichikawa, Yasuko Matsumoto, Kunio Fujii, Kiyotaka Saya, Hideyuki |
| description | Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients. |
| doi_str_mv | 10.1074/jbc.M503707200 |
| format | article |
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Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M503707200</identifier><identifier>PMID: 16169856</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Actin Depolymerizing Factors - physiology ; Actins - chemistry ; Actins - physiology ; Base Sequence ; Cell Line ; Cell Movement - physiology ; DNA-Binding Proteins - physiology ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Lim Kinases ; Neurofibromatosis 1 - genetics ; Neurofibromatosis 1 - physiopathology ; Neurofibromin 1 - antagonists & inhibitors ; Neurofibromin 1 - chemistry ; Neurofibromin 1 - genetics ; Neurofibromin 1 - physiology ; Phenotype ; Protein-Serine-Threonine Kinases - physiology ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; rho GTP-Binding Proteins - physiology ; rho-Associated Kinases ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Small Interfering - genetics ; Signal Transduction</subject><ispartof>The Journal of biological chemistry, 2005-11, Vol.280 (47), p.39524-39533</ispartof><rights>2005 © 2005 ASBMB. 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Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.</description><subject>Actin Depolymerizing Factors - physiology</subject><subject>Actins - chemistry</subject><subject>Actins - physiology</subject><subject>Base Sequence</subject><subject>Cell Line</subject><subject>Cell Movement - physiology</subject><subject>DNA-Binding Proteins - physiology</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Lim Kinases</subject><subject>Neurofibromatosis 1 - genetics</subject><subject>Neurofibromatosis 1 - physiopathology</subject><subject>Neurofibromin 1 - antagonists & inhibitors</subject><subject>Neurofibromin 1 - chemistry</subject><subject>Neurofibromin 1 - genetics</subject><subject>Neurofibromin 1 - physiology</subject><subject>Phenotype</subject><subject>Protein-Serine-Threonine Kinases - physiology</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>rho GTP-Binding Proteins - physiology</subject><subject>rho-Associated Kinases</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Signal Transduction</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNqFkctq3DAYhUVpSaZptl0WLUp3nkryRfIyuLmRmSYME8hOyPI_YwXbmkhygp-lLxuFGUg3pQLxb75zdPkQ-krJnBKe_Xys9XyZk5QTzgj5gGaUiDRJc_rwEc0IYTQpWS6O0WfvH0lcWUmP0DEtaFGKvJihP-sW8G8Ynd2Y2tleBeuNx-tpB5jiSxgA3znbjDr8TZkBnw-tGjR4XEHX4aUNpjNhwvWEV7AdOxXMsMVnOg58YTrVwxDwr2lQvdEePxuFQzx41dpkdVvdJIvr5Q1LqljfxcCdCu2Lmr6gTxvVeTg9zBN0f3G-rq6Sxe3ldXW2SHROREgKznIQhS4ygBpURiDLVANCKZ4y1qQUlChJXdciV2UjuAIgjeYl5WVTxJ2eoB_73p2zTyP4IHvjdXyWGsCOXhZCUJox9l-QlimPvW_gfA9qZ713sJE7Z3rlJkmJfPMmozf57i0Gvh2ax7qH5h0_iIrA9z3Qmm37YhzI2ljdQi-ZIDLjMi1zlkVM7DGI__VswEmvDURPTYzoIBtr_nWFV7Nps8Y</recordid><startdate>20051125</startdate><enddate>20051125</enddate><creator>Ozawa, Tatsuya</creator><creator>Araki, Norie</creator><creator>Yunoue, Shunji</creator><creator>Tokuo, Hiroshi</creator><creator>Feng, Liping</creator><creator>Patrakitkomjorn, Siriporn</creator><creator>Hara, Toshihiro</creator><creator>Ichikawa, Yasuko</creator><creator>Matsumoto, Kunio</creator><creator>Fujii, Kiyotaka</creator><creator>Saya, Hideyuki</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20051125</creationdate><title>The Neurofibromatosis Type 1 Gene Product Neurofibromin Enhances Cell Motility by Regulating Actin Filament Dynamics via the Rho-ROCK-LIMK2-Cofilin Pathway</title><author>Ozawa, Tatsuya ; Araki, Norie ; Yunoue, Shunji ; Tokuo, Hiroshi ; Feng, Liping ; Patrakitkomjorn, Siriporn ; Hara, Toshihiro ; Ichikawa, Yasuko ; Matsumoto, Kunio ; Fujii, Kiyotaka ; Saya, Hideyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-6725e86c64eebea40e44ade8aa7322d31ea890bbb85a9d87aee0dc79179d679d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Actin Depolymerizing Factors - physiology</topic><topic>Actins - chemistry</topic><topic>Actins - physiology</topic><topic>Base Sequence</topic><topic>Cell Line</topic><topic>Cell Movement - physiology</topic><topic>DNA-Binding Proteins - physiology</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Lim Kinases</topic><topic>Neurofibromatosis 1 - genetics</topic><topic>Neurofibromatosis 1 - physiopathology</topic><topic>Neurofibromin 1 - antagonists & inhibitors</topic><topic>Neurofibromin 1 - chemistry</topic><topic>Neurofibromin 1 - genetics</topic><topic>Neurofibromin 1 - physiology</topic><topic>Phenotype</topic><topic>Protein-Serine-Threonine Kinases - physiology</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>rho GTP-Binding Proteins - physiology</topic><topic>rho-Associated Kinases</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA, Small Interfering - genetics</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ozawa, Tatsuya</creatorcontrib><creatorcontrib>Araki, Norie</creatorcontrib><creatorcontrib>Yunoue, Shunji</creatorcontrib><creatorcontrib>Tokuo, Hiroshi</creatorcontrib><creatorcontrib>Feng, Liping</creatorcontrib><creatorcontrib>Patrakitkomjorn, Siriporn</creatorcontrib><creatorcontrib>Hara, Toshihiro</creatorcontrib><creatorcontrib>Ichikawa, Yasuko</creatorcontrib><creatorcontrib>Matsumoto, Kunio</creatorcontrib><creatorcontrib>Fujii, Kiyotaka</creatorcontrib><creatorcontrib>Saya, Hideyuki</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ozawa, Tatsuya</au><au>Araki, Norie</au><au>Yunoue, Shunji</au><au>Tokuo, Hiroshi</au><au>Feng, Liping</au><au>Patrakitkomjorn, Siriporn</au><au>Hara, Toshihiro</au><au>Ichikawa, Yasuko</au><au>Matsumoto, Kunio</au><au>Fujii, Kiyotaka</au><au>Saya, Hideyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Neurofibromatosis Type 1 Gene Product Neurofibromin Enhances Cell Motility by Regulating Actin Filament Dynamics via the Rho-ROCK-LIMK2-Cofilin Pathway</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2005-11-25</date><risdate>2005</risdate><volume>280</volume><issue>47</issue><spage>39524</spage><epage>39533</epage><pages>39524-39533</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16169856</pmid><doi>10.1074/jbc.M503707200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2005-11, Vol.280 (47), p.39524-39533 |
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| subjects | Actin Depolymerizing Factors - physiology Actins - chemistry Actins - physiology Base Sequence Cell Line Cell Movement - physiology DNA-Binding Proteins - physiology HeLa Cells Humans Intracellular Signaling Peptides and Proteins Lim Kinases Neurofibromatosis 1 - genetics Neurofibromatosis 1 - physiopathology Neurofibromin 1 - antagonists & inhibitors Neurofibromin 1 - chemistry Neurofibromin 1 - genetics Neurofibromin 1 - physiology Phenotype Protein-Serine-Threonine Kinases - physiology Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - metabolism rho GTP-Binding Proteins - physiology rho-Associated Kinases RNA, Messenger - genetics RNA, Messenger - metabolism RNA, Small Interfering - genetics Signal Transduction |
| title | The Neurofibromatosis Type 1 Gene Product Neurofibromin Enhances Cell Motility by Regulating Actin Filament Dynamics via the Rho-ROCK-LIMK2-Cofilin Pathway |
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