C‐Cbl regulates c‐MPL receptor trafficking and its internalization
Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c‐MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or m...
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2020-11, Vol.24 (21), p.12491-12503 |
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| creator | Märklin, Melanie Tandler, Claudia Kopp, Hans‐Georg Hoehn, Kyle L. Quintanilla‐Martinez, Leticia Borst, Oliver Müller, Martin R. Saur, Sebastian J. |
| description | Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c‐MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c‐Cbl which was previously shown to negatively regulated c‐MPL signalling. We developed a new conditional mouse model using c‐Cblfl/flPf4Cre mice and demonstrated that platelet‐specific knockout of c‐Cbl led to severe microthrombocytosis and impaired uptake of TPO and c‐MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c‐Cbl KO platelets. This study identified c‐Cbl as a potential player in causing megakaryocytic and thrombocytic disorders. |
| doi_str_mv | 10.1111/jcmm.15785 |
| format | Article |
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In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c‐Cbl which was previously shown to negatively regulated c‐MPL signalling. We developed a new conditional mouse model using c‐Cblfl/flPf4Cre mice and demonstrated that platelet‐specific knockout of c‐Cbl led to severe microthrombocytosis and impaired uptake of TPO and c‐MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c‐Cbl KO platelets. This study identified c‐Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.15785</identifier><identifier>PMID: 32954656</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Animals ; Antibodies ; Automation ; Blood platelets ; Bone marrow ; Cloning ; C‐Cbl ; c‐MPL ; Endocytosis ; Flow cytometry ; Glucose ; Integrases - metabolism ; Internalization ; Lymphocytosis ; megakaryocytes ; Megakaryocytes - metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Original ; Physiology ; Platelets ; Progenitor cells ; Protein Transport ; Proto-Oncogene Proteins c-cbl - metabolism ; Receptors, Thrombopoietin - metabolism ; Signal Transduction ; Stat5 protein ; Statistical analysis ; Stem cells ; Thrombocytopenia ; Thrombocytosis ; Thrombopoiesis ; Thrombopoietin ; Thrombopoietin - metabolism ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>Journal of cellular and molecular medicine, 2020-11, Vol.24 (21), p.12491-12503</ispartof><rights>2020 The Authors. published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</rights><rights>2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</rights><rights>2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4485-d5d3c23f93042aa5066a061b41b2c473b666c662ecd128ea254d5920b54cce533</citedby><cites>FETCH-LOGICAL-c4485-d5d3c23f93042aa5066a061b41b2c473b666c662ecd128ea254d5920b54cce533</cites><orcidid>0000-0002-2920-3894</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687000/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687000/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,1414,11549,27911,27912,45561,45562,46039,46463,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32954656$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Märklin, Melanie</creatorcontrib><creatorcontrib>Tandler, Claudia</creatorcontrib><creatorcontrib>Kopp, Hans‐Georg</creatorcontrib><creatorcontrib>Hoehn, Kyle L.</creatorcontrib><creatorcontrib>Quintanilla‐Martinez, Leticia</creatorcontrib><creatorcontrib>Borst, Oliver</creatorcontrib><creatorcontrib>Müller, Martin R.</creatorcontrib><creatorcontrib>Saur, Sebastian J.</creatorcontrib><title>C‐Cbl regulates c‐MPL receptor trafficking and its internalization</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c‐MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c‐Cbl which was previously shown to negatively regulated c‐MPL signalling. We developed a new conditional mouse model using c‐Cblfl/flPf4Cre mice and demonstrated that platelet‐specific knockout of c‐Cbl led to severe microthrombocytosis and impaired uptake of TPO and c‐MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c‐Cbl KO platelets. This study identified c‐Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Automation</subject><subject>Blood platelets</subject><subject>Bone marrow</subject><subject>Cloning</subject><subject>C‐Cbl</subject><subject>c‐MPL</subject><subject>Endocytosis</subject><subject>Flow cytometry</subject><subject>Glucose</subject><subject>Integrases - metabolism</subject><subject>Internalization</subject><subject>Lymphocytosis</subject><subject>megakaryocytes</subject><subject>Megakaryocytes - metabolism</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Original</subject><subject>Physiology</subject><subject>Platelets</subject><subject>Progenitor cells</subject><subject>Protein Transport</subject><subject>Proto-Oncogene Proteins c-cbl - metabolism</subject><subject>Receptors, Thrombopoietin - metabolism</subject><subject>Signal Transduction</subject><subject>Stat5 protein</subject><subject>Statistical analysis</subject><subject>Stem cells</subject><subject>Thrombocytopenia</subject><subject>Thrombocytosis</subject><subject>Thrombopoiesis</subject><subject>Thrombopoietin</subject><subject>Thrombopoietin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Märklin, Melanie</au><au>Tandler, Claudia</au><au>Kopp, Hans‐Georg</au><au>Hoehn, Kyle L.</au><au>Quintanilla‐Martinez, Leticia</au><au>Borst, Oliver</au><au>Müller, Martin R.</au><au>Saur, Sebastian J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C‐Cbl regulates c‐MPL receptor trafficking and its internalization</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2020-11</date><risdate>2020</risdate><volume>24</volume><issue>21</issue><spage>12491</spage><epage>12503</epage><pages>12491-12503</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c‐MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c‐Cbl which was previously shown to negatively regulated c‐MPL signalling. We developed a new conditional mouse model using c‐Cblfl/flPf4Cre mice and demonstrated that platelet‐specific knockout of c‐Cbl led to severe microthrombocytosis and impaired uptake of TPO and c‐MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c‐Cbl KO platelets. This study identified c‐Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>32954656</pmid><doi>10.1111/jcmm.15785</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2920-3894</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies Automation Blood platelets Bone marrow Cloning C‐Cbl c‐MPL Endocytosis Flow cytometry Glucose Integrases - metabolism Internalization Lymphocytosis megakaryocytes Megakaryocytes - metabolism Mice, Inbred C57BL Mice, Knockout Original Physiology Platelets Progenitor cells Protein Transport Proto-Oncogene Proteins c-cbl - metabolism Receptors, Thrombopoietin - metabolism Signal Transduction Stat5 protein Statistical analysis Stem cells Thrombocytopenia Thrombocytosis Thrombopoiesis Thrombopoietin Thrombopoietin - metabolism Ubiquitin Ubiquitin-protein ligase |
| title | C‐Cbl regulates c‐MPL receptor trafficking and its internalization |
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