C-Cbl regulates c-MPL receptor trafficking and its internalization.
Melanie Märklin, Claudia Tandler, Hans-Georg Kopp, Kyle L Hoehn, Leticia Quintanilla-Martinez, Oliver Borst, Martin R Müller, Sebastian J Saur
Author Information
Melanie Märklin: Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), University Hospital Tübingen, Tübingen, Germany. ORCID
Claudia Tandler: Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), University Hospital Tübingen, Tübingen, Germany.
Hans-Georg Kopp: Department of Molecular Oncology and Thoracic Oncology, Robert-Bosch-Hospital Stuttgart, Stuttgart, Germany.
Kyle L Hoehn: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
Leticia Quintanilla-Martinez: Department of Pathology, University of Tübingen, Tübingen, Germany.
Oliver Borst: Department of Kardiology and Angiology, University Hospital Tübingen, Tübingen, Germany.
Martin R Müller: Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
Sebastian J Saur: Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
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-Cbl Pf4 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.
