The Microtubule-Associated C-I Subfamily of TRIM Proteins and the Regulation of Polarized Cell Responses

  • Timothy C. Cox
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 770)


TRIM proteins are multidomain proteins that typically assemble into large molecular complexes, the composition of which likely explains the diverse functions that have been attributed to this group of proteins. Accumulating data on the roles of many TRIM proteins supports the notion that those that share identical C-terminal domain architectures participate in the regulation of similar cellular processes. At least nine different C-terminal domain compositions have been identified. This chapter will focus on one subgroup that possess a COS motif, FNIII and SPRY/B30.2 domain as their C-terminal domain arrangement. This C-terminal domain architecture plays a key role in the interaction of all six members of this subgroup with the microtubule cytoskeleton. Accumulating evidence on the functions of some of these proteins will be discussed to highlight the emerging similarities in the cellular events in which they participate.


Snare Complex Microtubule Cytoskeleton Ubiquitin Ligase Activity Trim Protein Vesicle Exocytosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Meroni G, Diez-Roux G. TRIM/RBCC, a novel class of’ single protein RING finger’ E3 ubiquitin ligases. Bioessays 2005; 27(11):1147–1157.PubMedGoogle Scholar
  2. 2.
    Reymond A, Meroni G, Fantozzi A et al. The tripartite motif family identifies cell compartments. EMBO J 2001;20(9):2140–2151.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Short KM, Cox TC. Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem 2006; 281(13):8970–8980.PubMedGoogle Scholar
  4. 4.
    Lerner M, Corcoran M, Cepeda D et al. The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Mol Biol Cell 2007; 18(5):1670–1682.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Palmer S, Perry J, Kipling D et al. A gene spans the pseudoautosomal boundary in mice. Proc Natl Acad Sci U S A 1997; 94(22):12030–12035.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Quaderi NA, Schweiger S, Gaudenz K et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet 1997; 17(3):285–291.PubMedGoogle Scholar
  7. 7.
    De Falco F, Cainarca S, Andolfi G et al. X-linked Opitz syndrome:novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A 2003; 120A(2):222–228.PubMedGoogle Scholar
  8. 8.
    So J, Suckow V, Kijas Z et al. Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. Am J Med Genet A 2005; 132A(1):1–7.PubMedGoogle Scholar
  9. 9.
    Cox TC, Allen LR, Cox LL et al. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum Mol Genet 2000; 9(17):2553–2562.PubMedGoogle Scholar
  10. 10.
    Liu J, Prickett TD, Elliott E et al. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Proc Natl Acad Sci U S A 2001; 98(12):6650–6655.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Short KM, Hopwood B, Yi Z et al. MID 1 and MID2 homo and heterodimerise to tetherthe rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules:implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. BMC Cell Biol 2002; 3(1):1.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Trockenbacher A, Suckow V, Foerster J et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 2001; 29(3):287–294.PubMedGoogle Scholar
  13. 13.
    Landry JR, Rouhi A, Medstrand P et al. The opitz syndrome gene mid1 is transcribed from a human endogenous retroviral promoter. Mol Biol Evol 2002; 19(11):1934–1942.PubMedGoogle Scholar
  14. 14.
    Dal Zotto L, Quaderi NA, Elliott R et al. The mouse Mid1 gene:implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region. Hum Mol Genet 1998; 7(3): 489–499.Google Scholar
  15. 15.
    Pinson L, Auge J, Audollent S et al. Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome. J Med Genet 2004; 41(5):381–386.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Richman JM, Fu KK, Cox LL et al. Isolation and characterisation of the chick orthologue of the Opitz syndrome gene, Mid1, supports a conserved role in vertebrate development. Int J Dev Biol 2002; 46(4): 441–448.PubMedGoogle Scholar
  17. 17.
    Suzuki M, Hara Y, Takagi C et al. MID1 and MID2 are required for Xenopus neural tube closure through the regulation of microtubule organization. Development 2010; 137(14):2329–2339.PubMedGoogle Scholar
  18. 18.
    Granata A, Quaderi NA. The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen’s node. Dev Biol 2003; 258(2):397–405.PubMedGoogle Scholar
  19. 19.
    Granata A, Savery D, Hazan J et al. Evidence of functional redundancy between MID proteins implications for the presentation of Opitz syndrome. Dev Biol 2005; 277(2):417–424.PubMedGoogle Scholar
  20. 20.
    Buchner G, Montini E, Andolfi G et al. MID2, a homologue of the Opitz syndrome gene MID1:similarities in subcellular localization and differences in expression during development. Hum Mol Genet 1999; 8(8): 1397–1407.PubMedGoogle Scholar
  21. 21.
    Perry J, Short KM, Romer JT et al. FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/ MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules. Genomics 1999; 62(3):385–394.PubMedGoogle Scholar
  22. 22.
    Cox TC. unpublished data.Google Scholar
  23. 23.
    Lancioni A, Pizzo M, Fontaneila B et al. Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis. J Neurosci 2010; 30(8):2880–2887.PubMedGoogle Scholar
  24. 24.
    Berti C, Fontaneila B, Ferrentino R et al. Mig 12, a novel Opitz syndrome gene product partner, is expressed in the embryonic ventral midline and co-operates with Mid1 to bundle and stabilize microtubules. BMC Cell Biol 2004; 5:9.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Conway G. A novel gene expressed during zebrafish gastrulation identified by differential RNA display. Mech Dev 1995; 52(2–3):383–391.PubMedGoogle Scholar
  26. 26.
    Hayes JM, Kim SK, Abitua PB et al. Identification of novel ciliogenesis factors using a new in vivo model for mucociliary epithelial development. Dev Biol 2007; 312(1): 115–130.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Aipoalani DL, O’Callaghan BL et al. Overlapping roles of the glucose-responsive genes, S14 and S14R, in hepatic lipogenesis. Endocrinology 2010; 151(5):2071–2077.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Inoue J, Yamasaki K, Ikeuchi E et al. Identification of MIG12 as a mediator for stimulation of lipogenesis by LXR activation. Mol Endocrinol 2011; 25(6):995–1005.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Kim CW, Moon YA, Park SW et al. Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc Natl Acad Sci U S A 2010; 107(21):9626–9631.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kong M, Ditsworth D, Lindsten T et al. Alpha4 is an essential regulator of PP2A phosphatase activity. Mol Cell 2009; 36(1):51–60.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Murata K, Wu J, Brautigan DL. B cell receptor-associated protein alpha 4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. PNAS 1997; 94(20): 10624–10629.PubMedGoogle Scholar
  32. 32.
    Nanahoshi M, Tsujishita Y, Tokunaga C et al. Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases. FEBS Lett 1999; 446(1):108–112.PubMedGoogle Scholar
  33. 33.
    Virshup DM, Shenolikar S. From promiscuity to precision:protein phosphatases get a makeover. Mol Cell 2009;33(5):537–545.PubMedGoogle Scholar
  34. 34.
    Prickett TD, Brautigan DL. The alpha4 regulatory subunit exerts opposing allosteric effects on protein phosphatases PP6 and PP2A. J Biol Chem 2006; 281(41):30503–30511.PubMedGoogle Scholar
  35. 35.
    McConnell JL, Watkins GR, Soss SE et al. Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination. Biochemistry 2010; 49(8):1713–1718.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Le Noue-Newton M, Watkins GR, Zou P et al. The E3 ubiquitin ligase and protein phosphatase 2A (PP2A)-binding domains of the Alpha4 protein are both required for Alpha4 to inhibit PP2A degradation. J Biol Chem 2011; 286(20):17665–17671.Google Scholar
  37. 37.
    Han X, Du H, Massiah MA. Detection and characterization of the in vitro e3 ligase activity of the human MID1 protein. J Mol Biol 2011; 407(4):505–520.PubMedGoogle Scholar
  38. 38.
    Liu E, Knutzen CA, Krauss S et al. Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 2011; 108(21):8680–8685.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Zoncu R, Efeyan A, Sabatini DM. mTOR:from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12(1):21–35.Google Scholar
  40. 40.
    Gayle SS, Arnold SL, O’Regan RM et al. Pharmacologie inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 2012; 12(2):151–162.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Hussein O, Tiedemann K, Murshed M et al. Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett 2012; 314(2): 176–184.PubMedGoogle Scholar
  42. 42.
    Trape AP, Katayama ML, Roela RA et al. Gene expression profile in response to doxorubicin-rapamycin combined treatment of HER-2-overexpressing human mammary epithelial cell lines. Mol Cancer Ther 2012; 11(2):464–474.PubMedGoogle Scholar
  43. 43.
    Dowling RJ, Topisirovic I, Fonseca BD et al. Dissecting the role of mTOR:lessons from mTOR inhibitors. Biochim Biophys Acta 2010; 1804(3):433–439.PubMedGoogle Scholar
  44. 44.
    Jiang Y, Broach JR. Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J 1999; 18(10):2782–2792.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Yan G, Shen X, Jiang Y. Rapamycin activates Tap42-associated phosphatases by abrogating their association with Tor complex 1. EMBO J 2006; 25(15):3546–3555.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003; 4(2): 117–126.PubMedGoogle Scholar
  47. 47.
    Yamashita T, Inui S, Maeda K et al. The heterodimer of alpha4 and PP2Ac is associated with S6 kinasel in B cells. Biochem Biophys Res Commun 2005; 330(2):439–445.PubMedGoogle Scholar
  48. 48.
    McDonald WJ, Sangster SM, Moffat LD et al. alpha4 phosphoprotein interacts with EDD E3 ubiquitin ligase and poly(A)-binding protein. J Cell Biochem 2010; 110(5): 1123–1129.PubMedGoogle Scholar
  49. 49.
    Aranda-Orgilles B, Trockenbacher A, Winter J et al. The Opitz syndrome gene product MID1 assembles a microtubule-associated ribonucleoprotein complex. Hum Genet 2008; 123(2): 163–176.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Aranda-Orgilles B, Rutschow D, Zeller R et al. Protein phosphatase 2A (PP2A)-specific ubiquitin ligase MID1 is a sequence-dependent regulator of translation efficiency controlling 3-phosphoinositide-dependent protein kinase-1 (PDPK-1). J Biol Chem 2011; 286(46):39945–39957.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998; 74:49–139.PubMedGoogle Scholar
  52. 52.
    Sutherland C. What Are the bona fide GSK3 Substrates? Int J Alzheimers Dis 2011; 2011:505607.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Aranda-Orgilles B, Aigner J, Kunath M et al. Active transport of the ubiquitin ligase MID1 along the microtubules is regulated by protein phosphatase 2A. PloS One 2008; 3(10):e3507.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Li Y, Chin LS, Weigel C et al. Spring, anovel RING finger protein that regulates synaptic vesicle exocytosis. J Biol Chem 2001; 276(44):40824–40833.PubMedGoogle Scholar
  55. 55.
    Chen YA, Scheller RH. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol 2001; 2(2):98–106.PubMedGoogle Scholar
  56. 56.
    Cahill AL, Herring BE, Fox AP. Stable silencing of SNAP-25 in PC12 cells by RNA interference. BMC Neurosci 2006; 7:9.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Tao-Cheng JH, Du J, McBain CJ. Snap-25 is polarized to axons and abundant along the axolemma:an immunogold study of intact neurons. J Neurocytol 2000; 29(1):67–77.PubMedGoogle Scholar
  58. 58.
    Dhingra V, Li X, Liu Y et al. Proteomic profiling reveals that rabies virus infection results in differential expression of host proteins involved in ion homeostasis and synaptic physiology in the central nervous system. J Neurovirol 2007; 13(2):107–117.PubMedGoogle Scholar
  59. 59.
    Tanji K, Kamitani T, Mori F et al. TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson’s disease and dementia with Lewy bodies. Neurobiol Dis 2010; 38(2):210–218.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Schlossmacher MG, Frosch MP, Gai WP et al. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. AM J Pathol 2002; 160(5): 1655–1667.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Spillantini MG, Schmidt ML, Lee VM et al. Alpha-synuclein in Lewy bodies. Nature 1997; 388(6645): 839–840.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Fanelli M, Fantozzi A, De Luca P et al. The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome. J Biol Chem 2004; 279(7):5374–5379.PubMedGoogle Scholar
  63. 63.
    Alexander M, Selman G, Seetharaman A et al. MADD-2, ahomolog of the Opitz syndrome protein MID1, regulates guidance to the midline through UNC-40 in Caenorhabditis elegans. Dev Cell 2010; 18(6):961–972.PubMedGoogle Scholar
  64. 64.
    Hao JC, Adler CE, Mebane L et al. The tripartite motif protein MADD-2 functions with the receptor UNC-40 (DCC) in Netrin-mediated axon attraction and branching. Dev Cell 2010; 18(6): 950–960.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Song S, Ge Q, Wang J et al. TRIM-9 functions in the UNC-6/UNC-40 pathway to regulate ventral guidance. J Genet Genomics 2011; 38(1):1–11.PubMedGoogle Scholar
  66. 66.
    Sun KLW, Correia JP, Kennedy TE. Netrins:versatile extracellular cues with diverse functions. Development 2011; 138(11):2153–2169.Google Scholar
  67. 67.
    Chang C, Adler CE, Krause M et al. MIG-10/lamellipodin and AGE-1/PI3K promote axon guidance and outgrowth in response to slit and netrin. Curr Biol 2006; 16(9):854–862.PubMedGoogle Scholar
  68. 68.
    Quinn CC, Pfeil DS, Chen E et al. UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin. Curr Biol 2006; 16(9):845–853.PubMedGoogle Scholar
  69. 69.
    Quinn CC, Wadsworth WG. Axon guidance:asymmetric signaling orients polarized outgrowth. Trends Cell Biol 2008; 18(12):597–603.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Tcherkezian J, Brittis PA, Thomas F et al. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 2010; 141(4):632–644.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Kitamura K, Tanaka H, Nishimune Y. Haprin, a novel haploid germ cell-specific RING finger protein involved in the acrosome reaction. J Biol Chem 2003; 278(45):44417–44423.PubMedGoogle Scholar
  72. 72.
    Kierszenbaum AL. Fusion of membranes during the acrosome reaction:atale oftwo SNAREs. Mol Reprod Dev 2000; 57(4):309–310.PubMedGoogle Scholar
  73. 73.
    Kitamura K, Tanaka H, Nishimune Y. The RING-fingerproteinhaprin:domains and function in the acrosome reaction. Curr Protein Pept Sci 2005; 6(6):567–574.PubMedGoogle Scholar
  74. 74.
    Cuykendall TN, Houston DW. Vegetally localized Xenopus trim36 regulates cortical rotation and dorsal axis formation. Development 2009; 136(18):3057–3065.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Yoshigai E, Kawamura S, Kuhara S et al. Trim36/Haprin plays a critical role in the arrangement of somites during Xenopus embryogenesis. Biochem Biophys Res Commun 2009; 378(3):428–432.PubMedGoogle Scholar
  76. 76.
    Kong M, Bui TV, Ditsworth D et al. The PP2 A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 2007; 282(40):29712–29720.PubMedGoogle Scholar
  77. 77.
    Miyajima N, Maruyama S, Nonomura K et al. TRIM36 interacts with the kinetochore protein CENP-H and delays cell cycle progression. Biochem Biophys Res Commun 2009; 381(3):383–387.PubMedGoogle Scholar
  78. 78.
    Sakamoto T, Uezu A, Kawauchi S et al. Mass spectrometric analysis of microtubule cosedimented proteins from rat brain. Genes Cells 2008; 13(4):295–312.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Timothy C. Cox
    • 1
    • 2
    • 3
  1. 1.Division of Craniofacial Medicine, Department of PediatricsUniversity of WashingtonUSA
  2. 2.Center for Tissue and Cell SciencesSeattle Children’s Research InstituteSeattleUSA
  3. 3.Department of Anatomy and Developmental BiologyMonash UniversityClaytonAustralia

Personalised recommendations