Endocytosis of Receptor Tyrosine Kinases
TL;DR: The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work.
Abstract: Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work.
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TL;DR: The Eph receptors are the largest of the RTK families and represent promising therapeutic targets, however, more research is needed to better understand the many aspects of their complex biology that remain mysterious.
Abstract: The Eph receptors have the prototypical RTK topology, with a multidomain extracellular region that includes the ephrin ligand-binding domain, a single transmembrane segment, and a cytoplasmic region that contains the kinase domain (Fig. 1). There are nine EphA receptors in the human genome, which promiscuously bind five ephrin-A ligands and five EphB receptors, which promiscuously bind three ephrin-B ligands (Pasquale 2004, 2005). Additionally, EphA4 and EphB2 can also bind ephrins of a different class. Two members of the family, EphA10 and EphB6, have modifications in conserved regions of their kinase domains that prevent kinase activity. Furthermore, a variety of alternatively spliced forms identified for many Eph receptors differ from the prototypical structure and have distinctive functions (Zisch and Pasquale 1997; Pasquale 2010).
Figure 1.
Domain structure of Eph receptors and ephrins.
Both ephrin classes include a conserved Eph receptor-binding domain, which is connected to the plasma membrane by a linker segment whose length can be affected by alternative splicing (Fig. 1). The ephrin-As are attached to the cell surface by a glycosylphosphatidylinositol (GPI) anchor, although they can also be released to activate EphA receptors at a distance (Bartley et al. 1994; Wykosky et al. 2008), whereas the ephrin-Bs contain a transmembrane segment and a short cytoplasmic region. Ephrin-A3 and ephrin-B3 also bind heparan sulfate proteoglycans through an interaction that involves their extracellular linker region and that, at least in the case of ephrin-A3, potentiates EphA receptor activation and signaling (Irie et al. 2008; Holen et al. 2011).
The Eph receptor family has greatly expanded during evolution, and includes almost one fourth of the 58 human RTKs (Schlessinger and Lemmon 2013). A large number of Eph receptors and ephrins may be required to achieve and maintain the sophisticated tissue organization of higher organisms. Indeed, many are highly expressed in the most complex organ, the brain, particularly during the establishment of its complex architecture and intricate wiring of neuronal connections (Yamaguchi and Pasquale 2004). Besides the brain, Eph receptors and ephrins are also present in most—if not all—other tissues, often in a combinatorial manner and with dynamically changing expression patterns (Pasquale 2005). In some regions, Eph receptors and ephrins are both coexpressed in the same cells, in others they have mutually exclusive expression patterns or they can be expressed in complementary gradients. These situations likely reflect different signaling modalities with different biological outcomes.
Eph receptors and ephrins engage in a multitude of activities. They typically mediate contact-dependent communication between cells of the same or different types to control cell morphology, adhesion, movement, proliferation, survival, and differentiation (Pasquale 2005). Through these activities, during development, the Eph/ephrin system plays a role in the spatial organization of different cell populations, axon guidance, formation of synaptic connections between neurons, and blood vessel remodeling. In the adult, the Eph/ephrin system regulates remodeling of synapses, epithelial differentiation and integrity, bone remodeling, immune function, insulin secretion, and stem cell self-renewal (Pasquale 2008; Genander and Frisen 2010). In addition, Eph receptors and ephrins are often up-regulated in injured tissues, where they inhibit some regenerative processes but promote angiogenesis, as well as in cancer cells, where they seem to be able to both promote and suppress tumorigenicity (Du et al. 2007; Pasquale 2008, 2010).
Here we provide an overview of Eph receptor and ephrin signaling mechanisms and biological effects, with an emphasis on recent findings. More detailed information on specific aspects of Eph receptor/ephrin biology and downstream signaling networks can be found in other recent reviews (Pasquale 2005, 2008, 2010; Arvanitis and Davy 2008; Lackmann and Boyd 2008; Klein 2009; Genander and Frisen 2010).
333 citations
Cites background from "Endocytosis of Receptor Tyrosine Ki..."
...Following ligand-dependent activation, RTKs are typically internalized by endocytosis and can continue to signal from intracellular compartments until they are inactivated by dephosphorylation and degradation or traffic back to the cell surface (Goh and Sorkin 2013)....
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TL;DR: The engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumours microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum are reported.
Abstract: Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.
260 citations
TL;DR: It is found that cell-cell contact is essential for the stability of the macrophage-fibroblast circuit, and principles of cell circuit design are illustrated and a quantitative perspective on cell interactions is provided.
230 citations
Cites background from "Endocytosis of Receptor Tyrosine Ki..."
...The most common mechanisms are autocrine growth factor production (Citri and Yarden, 2006) and removal of growth factors through receptor-mediated endocytosis (Goh and Sorkin, 2013)....
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...After growth factor binding, removal of growth factors from the environment through internalization of growth factor receptors has been well documented (Goh and Sorkin, 2013)....
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TL;DR: The data suggest the existence of a tissue microenvironment where stem cell factors influence cell survival, inflammation, angiogenesis, repair, and regeneration in a temporal and spatial manner.
Abstract: In the past decade, substantial evidence supports the paradigm that stem cells exert their reparative and regenerative effects, in large part, through the release of biologically active molecules acting in a paracrine fashion on resident cells. The data suggest the existence of a tissue microenvironment where stem cell factors influence cell survival, inflammation, angiogenesis, repair, and regeneration in a temporal and spatial manner.
212 citations
TL;DR: Using a split-ubiquitin yeast two-hybrid screen that covers a test-space of 6.4 × 106 pairs, 12,102 membrane/signaling protein interactions from Arabidopsis are identified, with several of the identified interactions fill gaps in important signal transduction chains, while others point to functions for enigmatic unknown proteins.
Abstract: Cellular membranes act as signaling platforms and control solute transport. Membrane receptors, transporters, and enzymes communicate with intracellular processes through protein-protein interactions. Using a split-ubiquitin yeast two-hybrid screen that covers a test-space of 6.4 × 10(6) pairs, we identified 12,102 membrane/signaling protein interactions from Arabidopsis. Besides confirmation of expected interactions such as heterotrimeric G protein subunit interactions and aquaporin oligomerization, >99% of the interactions were previously unknown. Interactions were confirmed at a rate of 32% in orthogonal in planta split-green flourescent protein interaction assays, which was statistically indistinguishable from the confirmation rate for known interactions collected from literature (38%). Regulatory associations in membrane protein trafficking, turnover, and phosphorylation include regulation of potassium channel activity through abscisic acid signaling, transporter activity by a WNK kinase, and a brassinolide receptor kinase by trafficking-related proteins. These examples underscore the utility of the membrane/signaling protein interaction network for gene discovery and hypothesis generation in plants and other organisms.
196 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.
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