Substrate specificity of receptor tyrosine kinases is critical for selective signaling

摘要: The completion of the human genome project has marked a new beginning in biomedical sciences. As cancer is genetic disease, field oncology been one first to be impacted by this historic revolution. High-throughput mutational profiling tumors provided an unprecedented amount information on changes leading and already revolutionized way lung cancers are classified treated. Fundamental for successfully translating uncovered these studies into clinic molecular and functional characterization identified lesions. part efforts, goal my thesis was gain an understanding how lesions affecting receptor tyrosine kinases (RTKs) contribute treatment response survival differences observed tumors. Phosphorylation tyrosine residues proteins described 1979 as activity of a viral transforming gene product. Soon afterwards RTKs were recognized play role in transducing growth factor signals across plasma membrane. Over past 50 years, the importance demonstrated multiple studies, increasing amounts data have implicated deregulation malfunction signaling variety of diseases including cancer. Although highly similar structure regulation, different RTKs exert distinct biological functions. ability function within common pathways, yet induce diverse phenotypic responses, largely attributed to: 1) cellular context, differentially expressed cell types; 2) strength and temporal properties signaling; 3) binding sites effector molecules. In addition mechanisms, we discovered that intrinsic RTK substrate specificity could also modulating functional among RTKs. In particular, we found SOCS3 residue Y165 be phosphorylated certain such the platelet derived (PDGFR) epidermal (EGFR). The increased phosphorylation leads ubiquitination proteasome-dependent degradation of SOCS3. major negative regulators IL-6 mediated signaling, of SOCS3 PDGFR-mediated results potentiation and phenotypically acquisition mesenchymal-like features metastatic potential as well erlotinib resistance.