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FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway
To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 d...
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| Published in: | Cancer cell 2007-09, Vol.12 (3), p.201-214 |
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| cites | cdi_FETCH-LOGICAL-c546t-53df2e7c9360ec5a7e0095683ad32e63fc3f9856c5a5045338fd2c847605d8423 |
| container_end_page | 214 |
| container_issue | 3 |
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| container_title | Cancer cell |
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| creator | Kang, Sumin Dong, Shaozhong Gu, Ting-Lei Guo, Ailan Cohen, Michael S. Lonial, Sagar Khoury, Hanna Jean Fabbro, Doriano Gilliland, D. Gary Bergsagel, P. Leif Taunton, Jack Polakiewicz, Roberto D. Chen, Jing |
| description | To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK. |
| doi_str_mv | 10.1016/j.ccr.2007.08.003 |
| format | article |
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Gary ; Bergsagel, P. Leif ; Taunton, Jack ; Polakiewicz, Roberto D. ; Chen, Jing</creator><creatorcontrib>Kang, Sumin ; Dong, Shaozhong ; Gu, Ting-Lei ; Guo, Ailan ; Cohen, Michael S. ; Lonial, Sagar ; Khoury, Hanna Jean ; Fabbro, Doriano ; Gilliland, D. Gary ; Bergsagel, P. Leif ; Taunton, Jack ; Polakiewicz, Roberto D. ; Chen, Jing</creatorcontrib><description>To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2007.08.003</identifier><identifier>PMID: 17785202</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Apoptosis ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic - metabolism ; CELLCYCLE ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Humans ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Kinases - metabolism ; Models, Biological ; Multiple Myeloma - enzymology ; Multiple Myeloma - metabolism ; Phosphorylation ; Receptor, Fibroblast Growth Factor, Type 3 - physiology ; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors ; Ribosomal Protein S6 Kinases, 90-kDa - metabolism ; RNA Interference ; SIGNALING ; Tyrosine - metabolism</subject><ispartof>Cancer cell, 2007-09, Vol.12 (3), p.201-214</ispartof><rights>2007 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-53df2e7c9360ec5a7e0095683ad32e63fc3f9856c5a5045338fd2c847605d8423</citedby><cites>FETCH-LOGICAL-c546t-53df2e7c9360ec5a7e0095683ad32e63fc3f9856c5a5045338fd2c847605d8423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17785202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kang, Sumin</creatorcontrib><creatorcontrib>Dong, Shaozhong</creatorcontrib><creatorcontrib>Gu, Ting-Lei</creatorcontrib><creatorcontrib>Guo, Ailan</creatorcontrib><creatorcontrib>Cohen, Michael S.</creatorcontrib><creatorcontrib>Lonial, Sagar</creatorcontrib><creatorcontrib>Khoury, Hanna Jean</creatorcontrib><creatorcontrib>Fabbro, Doriano</creatorcontrib><creatorcontrib>Gilliland, D. Gary</creatorcontrib><creatorcontrib>Bergsagel, P. Leif</creatorcontrib><creatorcontrib>Taunton, Jack</creatorcontrib><creatorcontrib>Polakiewicz, Roberto D.</creatorcontrib><creatorcontrib>Chen, Jing</creatorcontrib><title>FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.</description><subject>Apoptosis</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>CELLCYCLE</subject><subject>Enzyme Activation</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Humans</subject><subject>MAP Kinase Signaling System</subject><subject>Mitogen-Activated Protein Kinase Kinases - metabolism</subject><subject>Models, Biological</subject><subject>Multiple Myeloma - enzymology</subject><subject>Multiple Myeloma - metabolism</subject><subject>Phosphorylation</subject><subject>Receptor, Fibroblast Growth Factor, Type 3 - physiology</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - metabolism</subject><subject>RNA Interference</subject><subject>SIGNALING</subject><subject>Tyrosine - metabolism</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNqFUU1vEzEUXCEqWgo_gAvyiVu2z_ba6xUSUlUlLUorqhDOlvG-7TrarIPtBOU38KdxlfDRC5xszZuZZ88UxRsKJQUqL1altaFkAHUJqgTgz4ozqmo14VLJ5_kuuJhICuq0eBnjCrKG1s2L4pTWtRIM2FnxY3Y9W3ByaZPbmYSRLD7PGUme3GHrMkBucG2S33iHyVmyDGaMnQ8Zc34kqQ9--9CT5T746EYk972Pm96H_XAg-O5gaMb2144jnHokd9P5xXQxJ_cm9d_N_lVx0pkh4uvjeV58mU2XVzeT20_XH68ubydWVDJNBG87hrVtuAS0wtQI0AipuGk5Q8k7y7tGCZlHAirBuepaZlVVSxCtqhg_Lz4cfDfbr2tsLY4pmEFvglubsNfeOP10MrpeP_idZhWrKK2ywbujQfDfthiTXrtocRjMiH4btVSsylnDf4kMOG8YNJlID0Sbg4wBu9-voaAfu9YrnbvWj11rUDp3nTVv__7GH8Wx3Ex4fyBgDnPnMOhoHY42NxvQJt169w_7n_ePuuQ</recordid><startdate>20070901</startdate><enddate>20070901</enddate><creator>Kang, Sumin</creator><creator>Dong, Shaozhong</creator><creator>Gu, Ting-Lei</creator><creator>Guo, Ailan</creator><creator>Cohen, Michael S.</creator><creator>Lonial, Sagar</creator><creator>Khoury, Hanna Jean</creator><creator>Fabbro, Doriano</creator><creator>Gilliland, D. 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| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2007-09, Vol.12 (3), p.201-214 |
| issn | 1535-6108 1878-3686 |
| language | eng |
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| source | BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS |
| subjects | Apoptosis Binding Sites Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic - metabolism CELLCYCLE Enzyme Activation Extracellular Signal-Regulated MAP Kinases - metabolism Humans MAP Kinase Signaling System Mitogen-Activated Protein Kinase Kinases - metabolism Models, Biological Multiple Myeloma - enzymology Multiple Myeloma - metabolism Phosphorylation Receptor, Fibroblast Growth Factor, Type 3 - physiology Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors Ribosomal Protein S6 Kinases, 90-kDa - metabolism RNA Interference SIGNALING Tyrosine - metabolism |
| title | FGFR3 Activates RSK2 to Mediate Hematopoietic Transformation through Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway |
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