title: Engineering a single ubiquitin ligase for the selective degradation of all activated ErbB receptor tyrosine kinases.
abstract: Interrogating specific cellular activities often entails the dissection of posttranslational modifications or functional redundancy conferred by protein families, which demands more sophisticated research tools than simply eliminating a specific gene product by gene targeting or RNA interference. We have developed a novel methodology that involves engineering a single SCF(βTrCP)-based ubiquitin ligase that is capable of not only simultaneously targeting the entire family of ErbB receptor tyrosine kinases for ubiquitination and degradation, but also selectively recruiting only activated ErbBs. The engineered SCF(βTrCP) ubiquitin ligase effectively blocked ErbB signaling and attenuated oncogenicity in breast cancer cells, yet had little effect on the survival and growth of non-cancerous breast epithelial cells. Therefore, engineering ubiquitin ligases offers a simple research tool to dissect the specific traits of tumorigenic protein families, and provides a rapid and feasible means to expand the dimensionality of drug discovery by assessing protein families or posttranslational modifications as potential drug targets.
authors: 1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA [2] Key Laboratory of Cancer Prevention and Therapy, Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors: F
authors: F
authors: Kong
authors: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: J
authors: J
authors: Zhang
authors: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: Y
authors: Y
authors: Li
authors: Key Laboratory of Cancer Prevention and Therapy, Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors: X
authors: X
authors: Hao
authors: Key Laboratory of Cancer Prevention and Therapy, Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors: X
authors: X
authors: Ren
authors: Key Laboratory of Cancer Prevention and Therapy, Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors: H
authors: H
authors: Li
authors: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: P
authors: P
authors: Zhou
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015202:Protein Engineering; D059748:Proteolysis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases