Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44
CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavag...
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| Veröffentlicht in: | Oncogene 2003-03, Vol.22 (10), p.1511-1516 |
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| container_title | Oncogene |
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| creator | Murakami, Daizo Okamoto, Isamu Nagano, Osamu Kawano, Yoshiaki Tomita, Taisuke Iwatsubo, Takeshi De Strooper, Bart Yumoto, Eiji Saya, Hideyuki |
| description | CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent
γ
-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-
O
-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by
γ
-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/
γ
-secretase activity in the functional regulation of adhesion molecules. |
| doi_str_mv | 10.1038/sj.onc.1206298 |
| format | Article |
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γ
-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-
O
-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by
γ
-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/
γ
-secretase activity in the functional regulation of adhesion molecules.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1206298</identifier><identifier>PMID: 12629514</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Acetic acid ; Amyloid Precursor Protein Secretases ; Animals ; Apoptosis ; Aspartic Acid Endopeptidases ; Biological and medical sciences ; Carbamates - pharmacology ; CD44 antigen ; Cell adhesion molecules ; Cell Biology ; Cell Membrane - metabolism ; Cellular signal transduction ; Central Nervous System Neoplasms - drug therapy ; Central Nervous System Neoplasms - metabolism ; Dipeptides - pharmacology ; Embryo fibroblasts ; Embryo, Mammalian - cytology ; Endopeptidases - drug effects ; Endopeptidases - metabolism ; Extracellular matrix ; Fibroblasts - drug effects ; Fundamental and applied biological sciences. Psychology ; Glioma - drug therapy ; Glioma - metabolism ; Human Genetics ; Humans ; Hyaluronan Receptors - drug effects ; Hyaluronan Receptors - metabolism ; Internal Medicine ; Leupeptins - pharmacology ; Medicine ; Medicine & Public Health ; Membrane proteins ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Metastases ; Mice ; Mice, Knockout ; Molecular and cellular biology ; Oncology ; original-paper ; Pepstatins - pharmacology ; Physiological aspects ; Presenilin ; Presenilin 1 ; Protease Inhibitors - pharmacology ; Proteolysis ; Secretase ; Signal Transduction ; Tetradecanoylphorbol Acetate - pharmacology ; Transmembrane domains ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Oncogene, 2003-03, Vol.22 (10), p.1511-1516</ispartof><rights>Springer Nature Limited 2003</rights><rights>2003 INIST-CNRS</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Nature Publishing Group 2003.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-af7ac19fbb607e8987b8817e67c58982ca6b3eed368af839ff29ab01581ea1cc3</citedby><cites>FETCH-LOGICAL-c527t-af7ac19fbb607e8987b8817e67c58982ca6b3eed368af839ff29ab01581ea1cc3</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.1206298$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1206298$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14681039$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12629514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murakami, Daizo</creatorcontrib><creatorcontrib>Okamoto, Isamu</creatorcontrib><creatorcontrib>Nagano, Osamu</creatorcontrib><creatorcontrib>Kawano, Yoshiaki</creatorcontrib><creatorcontrib>Tomita, Taisuke</creatorcontrib><creatorcontrib>Iwatsubo, Takeshi</creatorcontrib><creatorcontrib>De Strooper, Bart</creatorcontrib><creatorcontrib>Yumoto, Eiji</creatorcontrib><creatorcontrib>Saya, Hideyuki</creatorcontrib><title>Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent
γ
-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-
O
-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by
γ
-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/
γ
-secretase activity in the functional regulation of adhesion molecules.</description><subject>Acetic acid</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Aspartic Acid Endopeptidases</subject><subject>Biological and medical sciences</subject><subject>Carbamates - pharmacology</subject><subject>CD44 antigen</subject><subject>Cell adhesion molecules</subject><subject>Cell Biology</subject><subject>Cell Membrane - metabolism</subject><subject>Cellular signal transduction</subject><subject>Central Nervous System Neoplasms - drug therapy</subject><subject>Central Nervous System Neoplasms - metabolism</subject><subject>Dipeptides - pharmacology</subject><subject>Embryo fibroblasts</subject><subject>Embryo, Mammalian - cytology</subject><subject>Endopeptidases - drug effects</subject><subject>Endopeptidases - metabolism</subject><subject>Extracellular matrix</subject><subject>Fibroblasts - drug effects</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glioma - drug therapy</subject><subject>Glioma - metabolism</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hyaluronan Receptors - drug effects</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Internal Medicine</subject><subject>Leupeptins - pharmacology</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane proteins</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular and cellular biology</subject><subject>Oncology</subject><subject>original-paper</subject><subject>Pepstatins - pharmacology</subject><subject>Physiological aspects</subject><subject>Presenilin</subject><subject>Presenilin 1</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Proteolysis</subject><subject>Secretase</subject><subject>Signal Transduction</subject><subject>Tetradecanoylphorbol Acetate - pharmacology</subject><subject>Transmembrane domains</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kc1q3DAUhUVpaaZpt10WQ2l3nkiyrZ9lmP5CoFmk0J24lq-mGmx5KmkCea6-R58pGmIYKAlCCEnfPTpXh5C3jK4ZbdRF2q3nYNeMU8G1ekZWrJWi7jrdPicrqjtaa97wM_IqpR2lVGrKX5IzxgvdsXZFfl1HTBj86EM94B7DgCFX__7WCW3EDAkrsNnf-nxXTTh4yJiq_BsrH3KECac-QpgPqbIjwi1ssZpdtfnUtq_JCwdjwjfLek5-fvl8s_lWX_34-n1zeVXbjstcg5NgmXZ9L6hEpZXslWIShbRd2XELom8Qh0YocKrRznENPWWdYgjM2uacfHzQ3cf5zwFTNpNPFscRAhZfhinJZNuIAr7_D9zNhxiKN8NFyxquqWpO1BZGND64ubRpj5LmkinNj5MXav0IVcaAk7dzQOfL-WMFNs4pRXRmH_0E8c4wao5BmrQzJUizBFkK3i1uD3359xO-JFeADwsAycLoSgzWpxPXClV0deEuHrhUrsIW46ntJ56-Bwxeth0</recordid><startdate>20030313</startdate><enddate>20030313</enddate><creator>Murakami, Daizo</creator><creator>Okamoto, Isamu</creator><creator>Nagano, Osamu</creator><creator>Kawano, Yoshiaki</creator><creator>Tomita, Taisuke</creator><creator>Iwatsubo, Takeshi</creator><creator>De Strooper, Bart</creator><creator>Yumoto, Eiji</creator><creator>Saya, Hideyuki</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20030313</creationdate><title>Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44</title><author>Murakami, Daizo ; Okamoto, Isamu ; Nagano, Osamu ; Kawano, Yoshiaki ; Tomita, Taisuke ; Iwatsubo, Takeshi ; De Strooper, Bart ; Yumoto, Eiji ; Saya, Hideyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-af7ac19fbb607e8987b8817e67c58982ca6b3eed368af839ff29ab01581ea1cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Acetic acid</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Aspartic Acid Endopeptidases</topic><topic>Biological and medical sciences</topic><topic>Carbamates - pharmacology</topic><topic>CD44 antigen</topic><topic>Cell adhesion molecules</topic><topic>Cell Biology</topic><topic>Cell Membrane - metabolism</topic><topic>Cellular signal transduction</topic><topic>Central Nervous System Neoplasms - drug therapy</topic><topic>Central Nervous System Neoplasms - metabolism</topic><topic>Dipeptides - pharmacology</topic><topic>Embryo fibroblasts</topic><topic>Embryo, Mammalian - cytology</topic><topic>Endopeptidases - drug effects</topic><topic>Endopeptidases - metabolism</topic><topic>Extracellular matrix</topic><topic>Fibroblasts - drug effects</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glioma - drug therapy</topic><topic>Glioma - metabolism</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hyaluronan Receptors - drug effects</topic><topic>Hyaluronan Receptors - metabolism</topic><topic>Internal Medicine</topic><topic>Leupeptins - pharmacology</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane proteins</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular and cellular biology</topic><topic>Oncology</topic><topic>original-paper</topic><topic>Pepstatins - pharmacology</topic><topic>Physiological aspects</topic><topic>Presenilin</topic><topic>Presenilin 1</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Proteolysis</topic><topic>Secretase</topic><topic>Signal Transduction</topic><topic>Tetradecanoylphorbol Acetate - pharmacology</topic><topic>Transmembrane domains</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murakami, Daizo</creatorcontrib><creatorcontrib>Okamoto, Isamu</creatorcontrib><creatorcontrib>Nagano, Osamu</creatorcontrib><creatorcontrib>Kawano, Yoshiaki</creatorcontrib><creatorcontrib>Tomita, Taisuke</creatorcontrib><creatorcontrib>Iwatsubo, Takeshi</creatorcontrib><creatorcontrib>De Strooper, Bart</creatorcontrib><creatorcontrib>Yumoto, Eiji</creatorcontrib><creatorcontrib>Saya, Hideyuki</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors 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CD44</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2003-03-13</date><risdate>2003</risdate><volume>22</volume><issue>10</issue><spage>1511</spage><epage>1516</epage><pages>1511-1516</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent
γ
-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-
O
-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by
γ
-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/
γ
-secretase activity in the functional regulation of adhesion molecules.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12629514</pmid><doi>10.1038/sj.onc.1206298</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2003-03, Vol.22 (10), p.1511-1516 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_18717436 |
| source | MEDLINE; Nature Journals Online; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | Acetic acid Amyloid Precursor Protein Secretases Animals Apoptosis Aspartic Acid Endopeptidases Biological and medical sciences Carbamates - pharmacology CD44 antigen Cell adhesion molecules Cell Biology Cell Membrane - metabolism Cellular signal transduction Central Nervous System Neoplasms - drug therapy Central Nervous System Neoplasms - metabolism Dipeptides - pharmacology Embryo fibroblasts Embryo, Mammalian - cytology Endopeptidases - drug effects Endopeptidases - metabolism Extracellular matrix Fibroblasts - drug effects Fundamental and applied biological sciences. Psychology Glioma - drug therapy Glioma - metabolism Human Genetics Humans Hyaluronan Receptors - drug effects Hyaluronan Receptors - metabolism Internal Medicine Leupeptins - pharmacology Medicine Medicine & Public Health Membrane proteins Membrane Proteins - genetics Membrane Proteins - metabolism Metastases Mice Mice, Knockout Molecular and cellular biology Oncology original-paper Pepstatins - pharmacology Physiological aspects Presenilin Presenilin 1 Protease Inhibitors - pharmacology Proteolysis Secretase Signal Transduction Tetradecanoylphorbol Acetate - pharmacology Transmembrane domains Tumor Cells, Cultured Tumors |
| title | Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44 |
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