Skip to main content
SpringerLink
Log in

dRAGging amino Acid-mTORC1 signaling by SH3BP4

  • Minireview
  • Published:
Molecules and Cells

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and autophagy. Its activity is regulated by the availability of amino acids and growth factors. The activation of mTORC1 by growth factors, such as insulin and insulin-like growth factor-1 (IGF-1), is mediated by tuberous sclerosis complex (TSC) 1 and 2 and Rheb GTPase. Relative to the growth factor-regulated mTORC1 pathway, the evolutionarily ancient amino acid-mTORC1 pathway remains not yet clearly defined. The amino acid-mTORC1 pathway is mediated by Rag GTPase heterodimers. Several binding proteins of Rag GTPases were discovered in recent studies. Here, we discuss the functions and mechanisms of the newly-identified binders of Rag GTPases. In particular, this review focuses on SH3 binding protein 4 (SH3BP4), the protein recently identifed as a negative regulator of Rag GTPases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bar-Peled, L., Schweitzer, L.D., Zoncu, R., and Sabatini, D.M. (2012). Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208.

    Article  PubMed  CAS  Google Scholar 

  • Beroukhim, R., Getz, G., Nghiemphu, L., Barretina, J., Hsueh, T., Linhart, D., Vivanco, I., Lee, J.C., Huang, J.H., et al. (2007). Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc. Natl. Acad. Sci. USA 104, 20007–20012.

    Article  PubMed  CAS  Google Scholar 

  • Beroukhim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J.S., Dobson, J., Urashima, M., et al. (2010). The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905.

    Article  PubMed  CAS  Google Scholar 

  • Binda, M., Peli-Gulli, M.P., Bonfils, G., Panchaud, N., Urban, J., Sturgill, T.W., Loewith, R., and De Virgilio, C. (2009). The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35, 563–573.

    Article  PubMed  CAS  Google Scholar 

  • Bonfils, G., Jaquenoud, M., Bontron, S., Ostrowicz, C., Ungermann, C., and De Virgilio, C. (2012). Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell 46, 105–110.

    Article  PubMed  CAS  Google Scholar 

  • Bryk, B., Hahn, K., Cohen, S.M., and Teleman, A.A. (2010). MAP4K3 regulates body size and metabolism in Drosophila. Dev. Biol. 344, 150–157.

    Article  PubMed  CAS  Google Scholar 

  • Chen, R.Q., Yang, Q.K., Lu, B.W., Yi, W., Cantin, G., Chen, Y.L., Fearns, C., Yates, J.R., 3rd, and Lee, J.D. (2009). CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res. 69, 2663–2668.

    Article  PubMed  CAS  Google Scholar 

  • Chiba, S., Tokuhara, M., Morita, E.H., and Abe, S. (2009). TTP at Ser245 phosphorylation by AKT is required for binding to 14-3-3. J. Biochem. 145, 403–409.

    Article  PubMed  CAS  Google Scholar 

  • Dubouloz, F., Deloche, O., Wanke, V., Cameroni, E., and De Virgilio, C. (2005). The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol. Cell 19, 15–26.

    Article  PubMed  CAS  Google Scholar 

  • Duran, A., Amanchy, R., Linares, J.F., Joshi, J., Abu-Baker, S., Porollo, A., Hansen, M., Moscat, J., and Diaz-Meco, M.T. (2011). p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell 44, 134–146.

    Article  PubMed  CAS  Google Scholar 

  • Findlay, G.M., Yan, L., Procter, J., Mieulet, V., and Lamb, R.F. (2007). A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem. J. 403, 13–20.

    Article  PubMed  CAS  Google Scholar 

  • Flinn, R.J., Yan, Y., Goswami, S., Parker, P.J., and Backer, J.M. (2010). The late endosome is essential for mTORC1 signaling. Mol. Biol. Cell 21, 833–841.

    Article  PubMed  CAS  Google Scholar 

  • Goberdhan, D.C., and Boyd, C.A. (2009). mTOR: dissecting regulation and mechanism of action to understand human disease. Biochem. Soc. Trans. 37, 213–216.

    Article  PubMed  CAS  Google Scholar 

  • Gong, R., Li, L., Liu, Y., Wang, P., Yang, H., Wang, L., Cheng, J., Guan, K.L., and Xu, Y. (2011). Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev. 25, 1668–1673.

    Article  PubMed  CAS  Google Scholar 

  • Han, J.M., Jeong, S.J., Park, M.C., Kim, G., Kwon, N.H., Kim, H.K., Ha, S.H., Ryu, S.H., and Kim, S. (2012). Leucyl-tRNA Synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424.

    Article  PubMed  CAS  Google Scholar 

  • Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189.

    Article  PubMed  CAS  Google Scholar 

  • Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C. S., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395.

    PubMed  CAS  Google Scholar 

  • Hennig, K.M., Colombani, J., and Neufeld, T.P. (2006). TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth. J. Cell Biol. 173, 963–974.

    Article  PubMed  CAS  Google Scholar 

  • Hirose, E., Nakashima, N., Sekiguchi, T., and Nishimoto, T. (1998). RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. J. Cell Sci. 111(Pt 1), 11–21.

    PubMed  CAS  Google Scholar 

  • Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K.L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657.

    Article  PubMed  CAS  Google Scholar 

  • Jeong, J.H., Lee, K.H., Kim, Y.M., Kim, D.H., Oh, B.H., and Kim, Y.G. (2012). Crystal structure of the Gtr1pGTP-Gtr2pGDP protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion. J. Biol. Chem. 287, 29648–29653.

    Article  PubMed  CAS  Google Scholar 

  • Jung, C.H., Ro, S.H., Cao, J., Otto, N.M., and Kim, D.H. (2010). mTOR regulation of autophagy. FEBS Lett. 584, 1287–1295.

    Article  PubMed  CAS  Google Scholar 

  • Kim, E., and Guan, K.L. (2009). RAG GTPases in nutrient-mediated TOR signaling pathway. Cell Cycle 8, 1014–1018.

    Article  PubMed  CAS  Google Scholar 

  • Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175.

    Article  PubMed  CAS  Google Scholar 

  • Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T.P., and Guan, K.L. (2008). Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945.

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y.M., Stone, M., Hwang, T.H., Kim, Y.G., Dunlevy, J.R., Griffin, T.J., and Kim, D.H. (2012). SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling. Mol. Cell 46, 833–846.

    Article  PubMed  CAS  Google Scholar 

  • Li, L., Kim, E., Yuan, H., Inoki, K., Goraksha-Hicks, P., Schiesher, R.L., Neufeld, T.P., and Guan, K.L. (2010). Regulation of mTORC1 by the Rab and Arf GTPases. J. Biol. Chem. 285, 19705–19709.

    Article  PubMed  CAS  Google Scholar 

  • Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J.L., Bonenfant, D., Oppliger, W., Jenoe, P., and Hall, M.N. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468.

    Article  PubMed  CAS  Google Scholar 

  • Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., and Avruch, J. (2005). Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713.

    Article  PubMed  CAS  Google Scholar 

  • Manning, B.D., and Cantley, L.C. (2003). Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28, 573–576.

    Article  PubMed  CAS  Google Scholar 

  • Narita, M., Young, A.R., Arakawa, S., Samarajiwa, S.A., Nakashima, T., Yoshida, S., Hong, S., Berry, L.S., Reichelt, S., Ferreira, M., et al. (2011). Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970.

    Article  PubMed  CAS  Google Scholar 

  • Nelson, N., Perzov, N., Cohen, A., Hagai, K., Padler, V., and Nelson, H. (2000). The cellular biology of proton-motive force generation by V-ATPases. J. Exp. Biol. 203, 89–95.

    PubMed  CAS  Google Scholar 

  • Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., et al. (2009). Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534.

    Article  PubMed  CAS  Google Scholar 

  • Pan, C., Gnad, F., Olsen, J.V., and Mann, M. (2008). Quantitative phosphoproteome analysis of a mouse liver cell line reveals specificity of phosphatase inhibitors. Proteomics 8, 4534–4546.

    Article  PubMed  CAS  Google Scholar 

  • Reddy, N.M., Potteti, H.R., Mariani, T.J., Biswal, S., and Reddy, S.P. (2011). Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am. J. Respir. Cell Mol. Biol. 45, 1161–1168.

    Article  PubMed  CAS  Google Scholar 

  • Resnik-Docampo, M., and de Celis, J.F. (2011). MAP4K3 is a component of the TORC1 signalling complex that modulates cell growth and viability in Drosophila melanogaster. PLoS One 6, e14528.

    Article  PubMed  CAS  Google Scholar 

  • Sancak, Y., Thoreen, C.C., Peterson, T.R., Lindquist, R.A., Kang, S.A., Spooner, E., Carr, S.A., and Sabatini, D.M. (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915.

    Article  PubMed  CAS  Google Scholar 

  • Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501.

    Article  PubMed  CAS  Google Scholar 

  • Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S., and Sabatini, D.M. (2010). Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303.

    Article  PubMed  CAS  Google Scholar 

  • Sekiguchi, T., Hirose, E., Nakashima, N., Ii, M., and Nishimoto, T. (2001). Novel G proteins, Rag C and Rag D, interact with GTPbinding proteins, Rag A and Rag B. J. Biol. Chem. 276, 7246–7257.

    Article  PubMed  CAS  Google Scholar 

  • Selman, C., Tullet, J.M., Wieser, D., Irvine, E., Lingard, S.J., Choudhury, A.I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144.

    Article  PubMed  CAS  Google Scholar 

  • Tee, A.R., Manning, B.D., Roux, P.P., Cantley, L.C., and Blenis, J. (2003). Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268.

    Article  PubMed  CAS  Google Scholar 

  • Tosoni, D., Puri, C., Confalonieri, S., Salcini, A.E., De Camilli, P., Tacchetti, C., and Di Fiore, P.P. (2005). TTP specifically regulates the internalization of the transferrin receptor. Cell 123, 875–888.

    Article  PubMed  CAS  Google Scholar 

  • Um, S.H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P.R., Kozma, S.C., Auwerx, J., et al. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205.

    Article  PubMed  CAS  Google Scholar 

  • Valbuena, N., Guan, K.L., and Moreno, S. (2012). The Vam6 and Gtr1-Gtr2 pathway activates TORC1 in response to amino acids in fission yeast. J. Cell Sci. 125, 1920–1928.

    Article  PubMed  CAS  Google Scholar 

  • Vander Haar, E., Lee, S.I., Bandhakavi, S., Griffin, T.J., and Kim, D.H. (2007). Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323.

    Article  Google Scholar 

  • Wullschleger, S., Loewith, R., and Hall, M.N. (2006). TOR signaling in growth and metabolism. Cell 124, 471–484.

    Article  PubMed  CAS  Google Scholar 

  • Wurmser, A.E., Sato, T.K., and Emr, S.D. (2000). New component of the vacuolar class C-Vps complex couples nucleotide exchange on the Ypt7 GTPase to SNARE-dependent docking and fusion. J. Cell Biol. 151, 551–562.

    Article  PubMed  CAS  Google Scholar 

  • Yan, L., Mieulet, V., Burgess, D., Findlay, G.M., Sully, K., Procter, J., Goris, J., Janssens, V., Morrice, N.A., and Lamb, R.F. (2010). PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR. Mol. Cell 37, 633–642.

    Article  PubMed  CAS  Google Scholar 

  • Yu, L., McPhee, C.K., Zheng, L., Mardones, G.A., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., et al. (2010). Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y., Gao, X., Saucedo, L.J., Ru, B., Edgar, B.A., and Pan, D. (2003). Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5, 578–581.

    Article  PubMed  CAS  Google Scholar 

  • Zoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., and Sabatini, D.M. (2011). mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar HATPase. Science 334, 678–683.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA

    Young-Mi Kim & Do-Hyung Kim

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA

    Do-Hyung Kim

Authors
  1. Young-Mi Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Do-Hyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Do-Hyung Kim.

About this article

Cite this article

Kim, YM., Kim, DH. dRAGging amino Acid-mTORC1 signaling by SH3BP4. Mol Cells 35, 1–6 (2013). https://doi.org/10.1007/s10059-013-2249-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-013-2249-1

Keywords

Search

Navigation