Mechanisms of RTK signal transduction across the plasma membrane

Receptor Tyrosine Kinase;Signal Transduction;FRET;Dimerization;Plasma membrane;Membrane proteins;Biophysics

Sarabipour, SarvenazWirtz, Denis ;

Johns Hopkins University

关键词: Receptor Tyrosine Kinase;    Signal Transduction;    FRET;    Dimerization;    Plasma membrane;    Membrane proteins;    Biophysics;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39367/SARABIPOUR-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Receptor Tyrosine kinases (RTKs) are a family of membrane proteins with extracellular ligand-binding domains, single transmembrane domains, and intracellular kinase domains. RTKs conduct biochemical signals upon lateral dimerization in the plasma membrane.While RTK activation is postulated to occur in response to ligand binding, recent work suggests that some RTKs are capable of forming ligand-independent dimers. However, the biological significance of RTK unliganded dimers is not well established, and the mechanistic knowledge of RTK signal transduction is incomplete. Here we use a methodology that has been specifically developed to study unliganded dimers, in order to further our understanding of RTK signal transduction across the plasma membrane. We show that the Fibroblast growth factor receptors, FGFRs,and Vascular endothelial growth factor receptor 2, VEGFR2, form dimers in the absence of their ligands, and we measure the unliganded dimer stabilities. We show that the transmembrane and intracellular domains favor dimerization, while the extracellular domains inhibit dimerization. We demonstrate that the unliganded dimers are phosphorylated. We further show that the unliganded dimers undergo structural changes in response to ligand binding, and this response depends on the identity of the ligand. Such structural changes appear to be a critical aspect of FGFR and VEGFR2 signal transduction across the plasma membrane.The FGF receptors and VEGF receptor 2 harbor many pathogenic mutations, but the effects of these mutations on signal transduction are not well understood. Here we study five different pathogenic mutations, linked to cancers and growth disorders, and show that these different mutations alter the mechanism of signal transduction in profoundly different ways. Thus, our results provide new basic knowledge about RTK signal transduction across the plasma membrane in health and disease.