Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface
Studies have shown that mutant calreticulin (CALR) constitutively activates the thrombopoietin (TPO) receptor MPL and thus plays a causal role in the development of myeloproliferative neoplasms (MPNs). To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we stu...
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| Veröffentlicht in: | Leukemia 2020-02, Vol.34 (2), p.499-509 |
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| creator | Masubuchi, Nami Araki, Marito Yang, Yinjie Hayashi, Erina Imai, Misa Edahiro, Yoko Hironaka, Yumi Mizukami, Yoshihisa Kihara, Yoshihiko Takei, Hiraku Nudejima, Mai Koike, Masato Ohsaka, Akimichi Komatsu, Norio |
| description | Studies have shown that mutant calreticulin (CALR) constitutively activates the thrombopoietin (TPO) receptor MPL and thus plays a causal role in the development of myeloproliferative neoplasms (MPNs). To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we studied the subcellular localization of mutant CALR and its importance for the oncogenic properties of mutant CALR. Here, mutant CALR accumulated in the Golgi apparatus, and its entrance into the secretion pathway and capacity to interact with N-glycan were required for its oncogenic capacity via the constitutive activation of MPL. Mutant CALR-dependent MPL activation was resistant to blockade of intracellular protein trafficking, suggesting that MPL is activated before reaching the cell surface. However, removal of MPL from the cell surface with trypsin shut down downstream activation, implying that the surface localization of MPL is required for mutant CALR-dependent activation. Furthermore, we found that mutant CALR and MPL interact on the cell surface. Based on these findings, we propose a model in which mutant CALR induces MPL activation on the cell surface to promote MPN development. |
| doi_str_mv | 10.1038/s41375-019-0564-z |
| format | Article |
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To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we studied the subcellular localization of mutant CALR and its importance for the oncogenic properties of mutant CALR. Here, mutant CALR accumulated in the Golgi apparatus, and its entrance into the secretion pathway and capacity to interact with N-glycan were required for its oncogenic capacity via the constitutive activation of MPL. Mutant CALR-dependent MPL activation was resistant to blockade of intracellular protein trafficking, suggesting that MPL is activated before reaching the cell surface. However, removal of MPL from the cell surface with trypsin shut down downstream activation, implying that the surface localization of MPL is required for mutant CALR-dependent activation. Furthermore, we found that mutant CALR and MPL interact on the cell surface. Based on these findings, we propose a model in which mutant CALR induces MPL activation on the cell surface to promote MPN development.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-019-0564-z</identifier><identifier>PMID: 31462733</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/31 ; 13/95 ; 14/19 ; 631/67/1990/2331 ; 631/80/86 ; 82/80 ; Antibodies ; Calcium-binding proteins ; Calreticulin ; Calreticulin - genetics ; Cancer Research ; Cell activation ; Cell culture ; Cell Line ; Cell surface ; Cell Transformation, Neoplastic - genetics ; Critical Care Medicine ; Development and progression ; Gene mutations ; Genetic aspects ; Glycan ; Golgi apparatus ; Health aspects ; Hematology ; Humans ; Intensive ; Internal Medicine ; Localization ; Medicine ; Medicine & Public Health ; Mutants ; Mutation ; Mutation - genetics ; Myelofibrosis ; Myeloproliferative Disorders - genetics ; Neoplasms ; Oncogenes ; Oncology ; Plasmids ; Protein transport ; Receptors, Thrombopoietin - genetics ; Secretion ; Secretory Pathway - genetics ; Shutdowns ; Signal Transduction - genetics ; Thrombocythemia ; Thrombocytosis ; Thrombopoietin ; Trypsin ; Trypsin - genetics ; Tumors ; University graduates</subject><ispartof>Leukemia, 2020-02, Vol.34 (2), p.499-509</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>2019© The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-9d8dab5e846fbcf80758bc3b2a20b3826e820510546dd4a7715bf82d87caae143</citedby><cites>FETCH-LOGICAL-c498t-9d8dab5e846fbcf80758bc3b2a20b3826e820510546dd4a7715bf82d87caae143</cites><orcidid>0000-0002-3174-5684 ; 0000-0002-3502-5000</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-019-0564-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-019-0564-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31462733$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Masubuchi, Nami</creatorcontrib><creatorcontrib>Araki, Marito</creatorcontrib><creatorcontrib>Yang, Yinjie</creatorcontrib><creatorcontrib>Hayashi, Erina</creatorcontrib><creatorcontrib>Imai, Misa</creatorcontrib><creatorcontrib>Edahiro, Yoko</creatorcontrib><creatorcontrib>Hironaka, Yumi</creatorcontrib><creatorcontrib>Mizukami, Yoshihisa</creatorcontrib><creatorcontrib>Kihara, Yoshihiko</creatorcontrib><creatorcontrib>Takei, Hiraku</creatorcontrib><creatorcontrib>Nudejima, Mai</creatorcontrib><creatorcontrib>Koike, Masato</creatorcontrib><creatorcontrib>Ohsaka, Akimichi</creatorcontrib><creatorcontrib>Komatsu, Norio</creatorcontrib><title>Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Studies have shown that mutant calreticulin (CALR) constitutively activates the thrombopoietin (TPO) receptor MPL and thus plays a causal role in the development of myeloproliferative neoplasms (MPNs). To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we studied the subcellular localization of mutant CALR and its importance for the oncogenic properties of mutant CALR. Here, mutant CALR accumulated in the Golgi apparatus, and its entrance into the secretion pathway and capacity to interact with N-glycan were required for its oncogenic capacity via the constitutive activation of MPL. Mutant CALR-dependent MPL activation was resistant to blockade of intracellular protein trafficking, suggesting that MPL is activated before reaching the cell surface. However, removal of MPL from the cell surface with trypsin shut down downstream activation, implying that the surface localization of MPL is required for mutant CALR-dependent activation. Furthermore, we found that mutant CALR and MPL interact on the cell surface. Based on these findings, we propose a model in which mutant CALR induces MPL activation on the cell surface to promote MPN development.</description><subject>13/1</subject><subject>13/31</subject><subject>13/95</subject><subject>14/19</subject><subject>631/67/1990/2331</subject><subject>631/80/86</subject><subject>82/80</subject><subject>Antibodies</subject><subject>Calcium-binding proteins</subject><subject>Calreticulin</subject><subject>Calreticulin - genetics</subject><subject>Cancer Research</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell Line</subject><subject>Cell surface</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Critical Care Medicine</subject><subject>Development and progression</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Glycan</subject><subject>Golgi apparatus</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Localization</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Myelofibrosis</subject><subject>Myeloproliferative Disorders - genetics</subject><subject>Neoplasms</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>Plasmids</subject><subject>Protein transport</subject><subject>Receptors, Thrombopoietin - genetics</subject><subject>Secretion</subject><subject>Secretory Pathway - genetics</subject><subject>Shutdowns</subject><subject>Signal Transduction - genetics</subject><subject>Thrombocythemia</subject><subject>Thrombocytosis</subject><subject>Thrombopoietin</subject><subject>Trypsin</subject><subject>Trypsin - genetics</subject><subject>Tumors</subject><subject>University 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calreticulin interacts with MPL in the secretion pathway for activation on the cell surface</title><author>Masubuchi, Nami ; Araki, Marito ; Yang, Yinjie ; Hayashi, Erina ; Imai, Misa ; Edahiro, Yoko ; Hironaka, Yumi ; Mizukami, Yoshihisa ; Kihara, Yoshihiko ; Takei, Hiraku ; Nudejima, Mai ; Koike, Masato ; Ohsaka, Akimichi ; Komatsu, Norio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-9d8dab5e846fbcf80758bc3b2a20b3826e820510546dd4a7715bf82d87caae143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/1</topic><topic>13/31</topic><topic>13/95</topic><topic>14/19</topic><topic>631/67/1990/2331</topic><topic>631/80/86</topic><topic>82/80</topic><topic>Antibodies</topic><topic>Calcium-binding proteins</topic><topic>Calreticulin</topic><topic>Calreticulin - genetics</topic><topic>Cancer Research</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Cell Line</topic><topic>Cell surface</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Critical Care Medicine</topic><topic>Development and progression</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Glycan</topic><topic>Golgi apparatus</topic><topic>Health aspects</topic><topic>Hematology</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Localization</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mutants</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Myelofibrosis</topic><topic>Myeloproliferative Disorders - genetics</topic><topic>Neoplasms</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>Plasmids</topic><topic>Protein transport</topic><topic>Receptors, Thrombopoietin - genetics</topic><topic>Secretion</topic><topic>Secretory Pathway - genetics</topic><topic>Shutdowns</topic><topic>Signal Transduction - genetics</topic><topic>Thrombocythemia</topic><topic>Thrombocytosis</topic><topic>Thrombopoietin</topic><topic>Trypsin</topic><topic>Trypsin - genetics</topic><topic>Tumors</topic><topic>University graduates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Masubuchi, Nami</creatorcontrib><creatorcontrib>Araki, Marito</creatorcontrib><creatorcontrib>Yang, Yinjie</creatorcontrib><creatorcontrib>Hayashi, Erina</creatorcontrib><creatorcontrib>Imai, Misa</creatorcontrib><creatorcontrib>Edahiro, Yoko</creatorcontrib><creatorcontrib>Hironaka, Yumi</creatorcontrib><creatorcontrib>Mizukami, Yoshihisa</creatorcontrib><creatorcontrib>Kihara, Yoshihiko</creatorcontrib><creatorcontrib>Takei, Hiraku</creatorcontrib><creatorcontrib>Nudejima, Mai</creatorcontrib><creatorcontrib>Koike, Masato</creatorcontrib><creatorcontrib>Ohsaka, Akimichi</creatorcontrib><creatorcontrib>Komatsu, Norio</creatorcontrib><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>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health 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China</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Masubuchi, Nami</au><au>Araki, Marito</au><au>Yang, Yinjie</au><au>Hayashi, Erina</au><au>Imai, Misa</au><au>Edahiro, Yoko</au><au>Hironaka, Yumi</au><au>Mizukami, Yoshihisa</au><au>Kihara, Yoshihiko</au><au>Takei, Hiraku</au><au>Nudejima, Mai</au><au>Koike, Masato</au><au>Ohsaka, Akimichi</au><au>Komatsu, Norio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2020-02-01</date><risdate>2020</risdate><volume>34</volume><issue>2</issue><spage>499</spage><epage>509</epage><pages>499-509</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Studies have shown that mutant calreticulin (CALR) constitutively activates the thrombopoietin (TPO) receptor MPL and thus plays a causal role in the development of myeloproliferative neoplasms (MPNs). To further elucidate the molecular mechanism by which mutant CALR promotes MPN development, we studied the subcellular localization of mutant CALR and its importance for the oncogenic properties of mutant CALR. Here, mutant CALR accumulated in the Golgi apparatus, and its entrance into the secretion pathway and capacity to interact with N-glycan were required for its oncogenic capacity via the constitutive activation of MPL. Mutant CALR-dependent MPL activation was resistant to blockade of intracellular protein trafficking, suggesting that MPL is activated before reaching the cell surface. However, removal of MPL from the cell surface with trypsin shut down downstream activation, implying that the surface localization of MPL is required for mutant CALR-dependent activation. Furthermore, we found that mutant CALR and MPL interact on the cell surface. Based on these findings, we propose a model in which mutant CALR induces MPL activation on the cell surface to promote MPN development.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31462733</pmid><doi>10.1038/s41375-019-0564-z</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3174-5684</orcidid><orcidid>https://orcid.org/0000-0002-3502-5000</orcidid></addata></record> |
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| ispartof | Leukemia, 2020-02, Vol.34 (2), p.499-509 |
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| subjects | 13/1 13/31 13/95 14/19 631/67/1990/2331 631/80/86 82/80 Antibodies Calcium-binding proteins Calreticulin Calreticulin - genetics Cancer Research Cell activation Cell culture Cell Line Cell surface Cell Transformation, Neoplastic - genetics Critical Care Medicine Development and progression Gene mutations Genetic aspects Glycan Golgi apparatus Health aspects Hematology Humans Intensive Internal Medicine Localization Medicine Medicine & Public Health Mutants Mutation Mutation - genetics Myelofibrosis Myeloproliferative Disorders - genetics Neoplasms Oncogenes Oncology Plasmids Protein transport Receptors, Thrombopoietin - genetics Secretion Secretory Pathway - genetics Shutdowns Signal Transduction - genetics Thrombocythemia Thrombocytosis Thrombopoietin Trypsin Trypsin - genetics Tumors University graduates |
| title | Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface |
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