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.

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Available from: Joseph Tcherkezian, May 20, 2014
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    • "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). "
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    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
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    • "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. "
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    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
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    • "Puromycin treatment strongly reduced polysome assembly and concomitantly shifted a substantial amount of LARP1 from polysomal to subpolysomal fractions (Supplemental Fig. 3A,B). While components of the eIF4F complex were, as expected, primarily associated with the 40S subunit (Tcherkezian et al. 2010), we found that the sedimentation of several ribosomal proteins was also dependent on mTOR activity, as shown for rpL5 and rpS6 (Fig. 4A,B). Interestingly, LARP1 and PABP showed very similar distributions, suggesting a possible interplay between these proteins. "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) promotes cell growth and proliferation by promoting mRNA translation and increasing the protein synthetic capacity of the cell. Although mTOR globally promotes translation by regulating the mRNA 5' cap-binding protein eIF4E (eukaryotic initiation factor 4E), it also preferentially regulates the translation of certain classes of mRNA via unclear mechanisms. To help fill this gap in knowledge, we performed a quantitative proteomic screen to identify proteins that associate with the mRNA 5' cap in an mTOR-dependent manner. Using this approach, we identified many potential regulatory factors, including the putative RNA-binding protein LARP1 (La-related protein 1). Our results indicate that LARP1 associates with actively translating ribosomes via PABP and that LARP1 stimulates the translation of mRNAs containing a 5' terminal oligopyrimidine (TOP) motif, encoding for components of the translational machinery. We found that LARP1 associates with the mTOR complex 1 (mTORC1) and is required for global protein synthesis as well as cell growth and proliferation. Together, these data reveal important molecular mechanisms involved in TOP mRNA translation and implicate LARP1 as an important regulator of cell growth and proliferation.
    Genes & development 02/2014; 28(4):357-71. DOI:10.1101/gad.231407.113 · 10.80 Impact Factor
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