Transmembrane Receptor DCC Associates with Protein Synthesis Machinery and Regulates Translation

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 05/2010; 141(4):632-44. DOI: 10.1016/j.cell.2010.04.008
Source: PubMed


Extracellular signals regulate protein translation in many cell functions. A key advantage of control at the translational level is the opportunity to regulate protein synthesis within specific cellular subregions. However, little is known about mechanisms that may link extracellular cues to translation with spatial precision. Here, we show that a transmembrane receptor, DCC, forms a binding complex containing multiple translation components, including eukaryotic initiation factors, ribosomal large and small subunits, and monosomes. In neuronal axons and dendrites DCC colocalizes in particles with translation machinery, and newly synthesized protein. The extracellular ligand netrin promoted DCC-mediated translation and disassociation of translation components. The functional and physical association of a cell surface receptor with the translation machinery leads to a generalizable model for localization and extracellular regulation of protein synthesis, based on a transmembrane translation regulation complex.

Download full-text


Available from: Joseph Tcherkezian, May 20, 2014
18 Reads
  • Source
    • "The mechanisms of RNA localization, translation, and stability are coupled, and it is common for individual RNA-binding proteins to influence more than one of these processes (Dreyfuss et al., 2002). Other aspects that might be interesting for future investigation are the potential relationship with previously described RNA granules (Xing and Bassell, 2013; Yasuda et al., 2013), or cellsurface receptors (Tcherkezian et al., 2010), and whether APC is part of a constitutive mechanism of the growth cone machinery or might be regulated by extracellular cues. Besides its function as a cytoskeletal regulator, APC is well known as a component of the Wnt/b-catenin pathway, where it binds and regulates the degradation of b-catenin protein (Clevers and Nusse, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional signifi- cance remain unclear. We show APC is an RNA-bind- ing protein and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC- related functions, including microtubule organiza- tion, cell motility, cancer, and neurologic disease. Among the targets is b2B-tubulin, known to be required in human neuron and axon migration. We show b2B-tubulin is synthesized in axons and local- izes preferentially to dynamic microtubules in the growth cone periphery. APC binds the b2B-tubulin 30 UTR; experiments interfering with this interaction reduced b2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally related protein and RNA net- works, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits.
    Cell 07/2014; 158(2):368-382. DOI:10.1016/j.cell.2014.05.042 · 32.24 Impact Factor
  • Source
    • "At least one study directly addressed this question. Flanagan and colleagues showed that deleted in colorectal cancer-1 (DCC1), a single transmembrane cell-surface receptor for netrin-1, directly binds to ribosomes and translation initiation factors, and translation is promoted by ligand binding (Tcherkezian et al., 2010). As ribosomes and initiation factors are components of mRNPs such as stress granules (Erickson and Lykke-Andersen, 2011), their interaction with cellsurface receptors, which can be regulated by ligand-receptor interaction, provides a conceptually appealing mechanism of cue-mRNA specificity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function.
    Cell 03/2014; 157(1):26-40. DOI:10.1016/j.cell.2014.03.005 · 32.24 Impact Factor
    • "The machinery for protein synthesis localized in the axonal periphery may be organized and regulated in a distinct manner that is strikingly different from that in the cell body. According to a recent article (Tcherkezian et al., 2010), the growth cone netrin receptor called " deleted in colorectal carcinoma (DCC) " is physically associated with elements of the protein synthetic machinery such as monosomes, "
    [Show abstract] [Hide abstract]
    ABSTRACT: At the Nobel lecture for physiology in 1906, Ramón y Cajal famously stated that "the nerve elements possess reciprocal relationships in contiguity but not in continuity," summing up the neuron doctrine. Sixty years later, by the time the central dogma of molecular biology formulated the axis of genetic information flow from DNA to mRNA, and then to protein, it became obvious that neurons with extensive ramifications and long axons inevitably incur an innate problem: how can the effect of gene expression be extended from the nucleus to the remote and specific sites of the cell periphery? The most straightforward solution would be to deliver soma-produced proteins to the target sites. The influential discovery of axoplasmic flow has supported this scheme of protein supply. Alternatively, mRNAs can be dispatched instead of protein, and translated locally at the strategic target sites. Over the past decades, such a local system of protein synthesis has been demonstrated in dendrites, axons and presynaptic terminals. Moreover, the local protein synthesis in neurons might even involve intercellular trafficking of molecules. The innovative concept of glia-neuron unit suggests that the local protein synthesis in the axonal and presynaptic domain of mature neurons is sustained by a local supply of RNAs synthesized in the surrounding glial cells and transferred to these domains. Here, we have reviewed some of the evidence indicating the presence of a local system of protein synthesis in axon terminals, and have examined its regulation in various model systems. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Developmental Neurobiology 03/2014; 74(3). DOI:10.1002/dneu.22109 · 3.37 Impact Factor
Show more