Author
Philippe I. H. Bastiaens
Other affiliations: Technical University of Dortmund, Saarland University
Bio: Philippe I. H. Bastiaens is an academic researcher from Max Planck Society. The author has contributed to research in topics: Phosphorylation & Fluorescence-lifetime imaging microscopy. The author has an hindex of 56, co-authored 168 publications receiving 13323 citations. Previous affiliations of Philippe I. H. Bastiaens include Technical University of Dortmund & Saarland University.
Papers published on a yearly basis
Papers
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TL;DR: It is shown that the specific subcellular distribution of H- and Nras guanosine triphosphate–binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus.
Abstract: We show that the specific subcellular distribution of H- and Nras guanosine triphosphate-binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in all membranes, followed by repalmitoylation and trapping of Ras at the Golgi, from where it is redirected to the PM via the secretory pathway. This continuous cycle prevents Ras from nonspecific residence on endomembranes, thereby maintaining the specific intracellular compartmentalization. The de/reacylation cycle also initiates Ras activation at the Golgi by transport of PM-localized Ras guanosine triphosphate. Different de/repalmitoylation kinetics account for isoform-specific activation responses to growth factors.
797 citations
TL;DR: Fluorescence lifetime imaging microscopy is a technique in which the mean fluorescence lifetime of a chromophore is measured at each spatially resolvable element of a microscope image to allow exploration of the molecular environment of labelled macromolecules in the interior of cells.
698 citations
TL;DR: Results show that growth factor context determines the topology of the MAPK signalling network and that the resulting dynamics govern cell fate.
Abstract: The mitogen-activated protein kinase (MAPK) network is a conserved signalling module that regulates cell fate by transducing a myriad of growth-factor signals. The ability of this network to coordinate and process a variety of inputs from different growth-factor receptors into specific biological responses is, however, still not understood. We investigated how the MAPK network brings about signal specificity in PC-12 cells, a model for neuronal differentiation. Reverse engineering by modular-response analysis uncovered topological differences in the MAPK core network dependent on whether cells were activated with epidermal or neuronal growth factor (EGF or NGF). On EGF stimulation, the network exhibited negative feedback only, whereas a positive feedback was apparent on NGF stimulation. The latter allows for bi-stable Erk activation dynamics, which were indeed observed. By rewiring these regulatory feedbacks, we were able to reverse the specific cell responses to EGF and NGF. These results show that growth factor context determines the topology of the MAPK signalling network and that the resulting dynamics govern cell fate.
631 citations
TL;DR: This work has shown that the generation of sets of clones that express a representative of each protein of a proteome in a useful format followed by the analysis of these sets on a genome-wide basis enables genetic, biochemical and cell biological technologies to be applied on a systematic level.
Abstract: The long-term challenge of proteomics is enormous: to define the identities, quantities, structures and functions of complete complements of proteins, and to characterize how these properties vary in different cellular contexts. One critical step in tackling this goal is the generation of sets of clones that express a representative of each protein of a proteome in a useful format, followed by the analysis of these sets on a genome-wide basis. Such studies enable genetic, biochemical and cell biological technologies to be applied on a systematic level, leading to the assignment of biochemical activities, the construction of protein arrays, the identification of interactions, and the localization of proteins within cellular compartments.
608 citations
TL;DR: It is reported that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes.
Abstract: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEδ interaction that selectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.
522 citations
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TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
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TL;DR: Assessment of medical technology in the context of commercialization with Bioentrepreneur course, which addresses many issues unique to biomedical products.
Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.
4,833 citations
TL;DR: The important findings in the history of signal transduction are adequately covered in many reviews, and I have therefore cited reviews that discuss the seminal papers.
2,491 citations
TL;DR: This map serves as a starting point for a systems biology modeling of multicellular organisms, including humans, and recapitulated known pathways, extended pathways, and uncovered previously unknown pathway components.
Abstract: Drosophila melanogaster is a proven model system for many aspects of human biology. Here we present a two-hybrid-based protein-interaction map of the fly proteome. A total of 10,623 predicted transcripts were isolated and screened against standard and normalized complementary DNA libraries to produce a draft map of 7048 proteins and 20,405 interactions. A computational method of rating two-hybrid interaction confidence was developed to refine this draft map to a higher confidence map of 4679 proteins and 4780 interactions. Statistical modeling of the network showed two levels of organization: a short-range organization, presumably corresponding to multiprotein complexes, and a more global organization, presumably corresponding to intercomplex connections. The network recapitulated known pathways, extended pathways, and uncovered previously unknown pathway components. This map serves as a starting point for a systems biology modeling of multicellular organisms, including humans.
2,414 citations
TL;DR: Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades and the CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes.
Abstract: Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes — not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
2,171 citations