Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells
The chemokine-CXCL12 and its receptor, CXCR4, have recently been shown to play an important role in regulating the directional migration of breast cancer cells to sites of metastasis. In the present study, we showed that CXCL12 enhanced the chemotaxis, chemoinvasion and adhesive properties of breast...
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| Veröffentlicht in: | Oncogene 2004-01, Vol.23 (1), p.157-167 |
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| creator | Fernandis, Aaron Zefrin Prasad, Anil Band, Hamid Klösel, Roland Ganju, Ramesh Kumar |
| description | The chemokine-CXCL12 and its receptor, CXCR4, have recently been shown to play an important role in regulating the directional migration of breast cancer cells to sites of metastasis. In the present study, we showed that CXCL12 enhanced the chemotaxis, chemoinvasion and adhesive properties of breast cancer cells; parameters that are critical for development of metastasis. We have also evaluated the signaling mechanisms that regulate CXCL12-induced and CXCR4-mediated breast cancer cell motility and invasion. These studies revealed that CXCL12 induces the tyrosine phosphorylation of focal adhesion kinase (FAK) at residues 397 and 577, and of RAFTK/Pyk2 at residues 402 and 579/580. The cytoskeletal proteins paxillin and Crk, as well as tyrosine phosphatase SHP2 and adaptor protein Cbl, were also phosphorylated. CXCL12 induced the activation of PI 3-kinase, and increased its association with Cbl and SHP2. PI 3-kinase, RAFTK/Pyk2 and tyrosine phosphatase inhibitors significantly blocked CXCL12-induced chemotaxis and chemoinvasion. The role of SHP2 and Cbl in CXCL12-induced chemotaxis and chemoinvasion in breast cancer cells was further defined by transiently overexpressing wild-type SHP2, wild-type Cbl, dominant-negative SHP2, Cbl mutants 70Z/3 and G306E or double transfectants of the Cbl and SHP2 constructs. We found a novel role of Cbl in CXCL12-induced chemotaxis, which may be mediated through the activation and formation of a multimeric complex comprised of Cbl, SHP2 and PI 3-kinase. We also observed the activation of matrix metalloproteinases 2 and 9 upon CXCL12 stimulation. These studies provide new information regarding signaling pathways that may regulate CXCL12-induced metastasis in breast cancer cells. |
| doi_str_mv | 10.1038/sj.onc.1206910 |
| format | Article |
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In the present study, we showed that CXCL12 enhanced the chemotaxis, chemoinvasion and adhesive properties of breast cancer cells; parameters that are critical for development of metastasis. We have also evaluated the signaling mechanisms that regulate CXCL12-induced and CXCR4-mediated breast cancer cell motility and invasion. These studies revealed that CXCL12 induces the tyrosine phosphorylation of focal adhesion kinase (FAK) at residues 397 and 577, and of RAFTK/Pyk2 at residues 402 and 579/580. The cytoskeletal proteins paxillin and Crk, as well as tyrosine phosphatase SHP2 and adaptor protein Cbl, were also phosphorylated. CXCL12 induced the activation of PI 3-kinase, and increased its association with Cbl and SHP2. PI 3-kinase, RAFTK/Pyk2 and tyrosine phosphatase inhibitors significantly blocked CXCL12-induced chemotaxis and chemoinvasion. 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These studies provide new information regarding signaling pathways that may regulate CXCL12-induced metastasis in breast cancer cells.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1206910</identifier><identifier>PMID: 14712221</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - pathology ; Cell Adhesion ; Cell Biology ; Cell Line, Tumor ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Chemokine CXCL12 ; Chemokines, CXC - pharmacology ; Chemotaxis ; Female ; Focal Adhesion Kinase 1 ; Focal Adhesion Kinase 2 ; Focal Adhesion Protein-Tyrosine Kinases ; Fundamental and applied biological sciences. Psychology ; Gynecology. Andrology. Obstetrics ; Human Genetics ; Humans ; Internal Medicine ; Intracellular Signaling Peptides and Proteins ; Mammary gland diseases ; Matrix Metalloproteinase 2 - biosynthesis ; Matrix Metalloproteinase 9 - biosynthesis ; Medical sciences ; Medicine ; Medicine & Public Health ; Mitogen-Activated Protein Kinases - physiology ; Molecular and cellular biology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Oncology ; original-paper ; Phosphatidylinositol 3-Kinases - physiology ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases - physiology ; Protein-Tyrosine Kinases - metabolism ; Receptors, CXCR4 - physiology ; Tumors ; Tyrosine - metabolism</subject><ispartof>Oncogene, 2004-01, Vol.23 (1), p.157-167</ispartof><rights>Springer Nature Limited 2004</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2004 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 8, 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c614t-a869dae97dd927c8d09b6555a9d92ba28e0dbf9b18045e468ba7ddb6888c45113</citedby><cites>FETCH-LOGICAL-c614t-a869dae97dd927c8d09b6555a9d92ba28e0dbf9b18045e468ba7ddb6888c45113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1206910$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1206910$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,2725,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15673902$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14712221$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fernandis, Aaron Zefrin</creatorcontrib><creatorcontrib>Prasad, Anil</creatorcontrib><creatorcontrib>Band, Hamid</creatorcontrib><creatorcontrib>Klösel, Roland</creatorcontrib><creatorcontrib>Ganju, Ramesh Kumar</creatorcontrib><title>Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>The chemokine-CXCL12 and its receptor, CXCR4, have recently been shown to play an important role in regulating the directional migration of breast cancer cells to sites of metastasis. In the present study, we showed that CXCL12 enhanced the chemotaxis, chemoinvasion and adhesive properties of breast cancer cells; parameters that are critical for development of metastasis. We have also evaluated the signaling mechanisms that regulate CXCL12-induced and CXCR4-mediated breast cancer cell motility and invasion. These studies revealed that CXCL12 induces the tyrosine phosphorylation of focal adhesion kinase (FAK) at residues 397 and 577, and of RAFTK/Pyk2 at residues 402 and 579/580. The cytoskeletal proteins paxillin and Crk, as well as tyrosine phosphatase SHP2 and adaptor protein Cbl, were also phosphorylated. CXCL12 induced the activation of PI 3-kinase, and increased its association with Cbl and SHP2. PI 3-kinase, RAFTK/Pyk2 and tyrosine phosphatase inhibitors significantly blocked CXCL12-induced chemotaxis and chemoinvasion. The role of SHP2 and Cbl in CXCL12-induced chemotaxis and chemoinvasion in breast cancer cells was further defined by transiently overexpressing wild-type SHP2, wild-type Cbl, dominant-negative SHP2, Cbl mutants 70Z/3 and G306E or double transfectants of the Cbl and SHP2 constructs. We found a novel role of Cbl in CXCL12-induced chemotaxis, which may be mediated through the activation and formation of a multimeric complex comprised of Cbl, SHP2 and PI 3-kinase. We also observed the activation of matrix metalloproteinases 2 and 9 upon CXCL12 stimulation. These studies provide new information regarding signaling pathways that may regulate CXCL12-induced metastasis in breast cancer cells.</description><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Adhesion</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Chemokine CXCL12</subject><subject>Chemokines, CXC - pharmacology</subject><subject>Chemotaxis</subject><subject>Female</subject><subject>Focal Adhesion Kinase 1</subject><subject>Focal Adhesion Kinase 2</subject><subject>Focal Adhesion Protein-Tyrosine Kinases</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gynecology. Andrology. 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fernandis, Aaron Zefrin</au><au>Prasad, Anil</au><au>Band, Hamid</au><au>Klösel, Roland</au><au>Ganju, Ramesh Kumar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2004-01-08</date><risdate>2004</risdate><volume>23</volume><issue>1</issue><spage>157</spage><epage>167</epage><pages>157-167</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>The chemokine-CXCL12 and its receptor, CXCR4, have recently been shown to play an important role in regulating the directional migration of breast cancer cells to sites of metastasis. In the present study, we showed that CXCL12 enhanced the chemotaxis, chemoinvasion and adhesive properties of breast cancer cells; parameters that are critical for development of metastasis. We have also evaluated the signaling mechanisms that regulate CXCL12-induced and CXCR4-mediated breast cancer cell motility and invasion. These studies revealed that CXCL12 induces the tyrosine phosphorylation of focal adhesion kinase (FAK) at residues 397 and 577, and of RAFTK/Pyk2 at residues 402 and 579/580. The cytoskeletal proteins paxillin and Crk, as well as tyrosine phosphatase SHP2 and adaptor protein Cbl, were also phosphorylated. CXCL12 induced the activation of PI 3-kinase, and increased its association with Cbl and SHP2. PI 3-kinase, RAFTK/Pyk2 and tyrosine phosphatase inhibitors significantly blocked CXCL12-induced chemotaxis and chemoinvasion. The role of SHP2 and Cbl in CXCL12-induced chemotaxis and chemoinvasion in breast cancer cells was further defined by transiently overexpressing wild-type SHP2, wild-type Cbl, dominant-negative SHP2, Cbl mutants 70Z/3 and G306E or double transfectants of the Cbl and SHP2 constructs. We found a novel role of Cbl in CXCL12-induced chemotaxis, which may be mediated through the activation and formation of a multimeric complex comprised of Cbl, SHP2 and PI 3-kinase. We also observed the activation of matrix metalloproteinases 2 and 9 upon CXCL12 stimulation. These studies provide new information regarding signaling pathways that may regulate CXCL12-induced metastasis in breast cancer cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>14712221</pmid><doi>10.1038/sj.onc.1206910</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Nature; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | Apoptosis Biological and medical sciences Breast cancer Breast Neoplasms - pathology Cell Adhesion Cell Biology Cell Line, Tumor Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Chemokine CXCL12 Chemokines, CXC - pharmacology Chemotaxis Female Focal Adhesion Kinase 1 Focal Adhesion Kinase 2 Focal Adhesion Protein-Tyrosine Kinases Fundamental and applied biological sciences. Psychology Gynecology. Andrology. Obstetrics Human Genetics Humans Internal Medicine Intracellular Signaling Peptides and Proteins Mammary gland diseases Matrix Metalloproteinase 2 - biosynthesis Matrix Metalloproteinase 9 - biosynthesis Medical sciences Medicine Medicine & Public Health Mitogen-Activated Protein Kinases - physiology Molecular and cellular biology Neoplasm Invasiveness Neoplasm Metastasis Oncology original-paper Phosphatidylinositol 3-Kinases - physiology Phosphorylation Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatases - physiology Protein-Tyrosine Kinases - metabolism Receptors, CXCR4 - physiology Tumors Tyrosine - metabolism |
| title | Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells |
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