Abstract
Nuclear receptors are ligand-activated transcription factors that partake in several biological processes including development, reproduction and metabolism. Over the last decade, evidence has accumulated that group 2, 3 and 4 LIM domain proteins, primarily known for their roles in actin cytoskeleton organization, also partake in gene transcription regulation. They shuttle between the cytoplasm and the nucleus, amongst other as a consequence of triggering cells with ligands of nuclear receptors. LIM domain proteins act as important coregulators of nuclear receptor-mediated gene transcription, in which they can either function as coactivators or corepressors. In establishing interactions with nuclear receptors, the LIM domains are important, yet pleiotropy of LIM domain proteins and nuclear receptors frequently occurs. LIM domain protein-nuclear receptor complexes function in diverse physiological processes. Their association is, however, often linked to diseases including cancer.
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Lee JS, Kim KI, Baek SH (2008) Nuclear receptors and coregulators in inflammation and cancer. Cancer Lett 267(2):189–196
Skerrett R, Malm T, Landreth G (2014) Nuclear receptors in neurodegenerative diseases. Neurobiol Dis 72(Part A):104–116
Schulman IG (2010) Nuclear receptors as drug targets for metabolic disease. Adv Drug Deliv Rev 62(13):1307–1315
Robinson-Rechavi M, Garcia HE, Laudet V (2003) The nuclear receptor superfamily. J Cell Sci 116(4):585–586
Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT (2007) Nuclear receptor structure: implications for function. Annu Rev Physiol 69(1):201–220
Heitzer MD, Wolf IM, Sanchez ER, Witchel SF, DeFranco DB (2007) Glucocorticoid receptor physiology. Rev Endocr Metab Disord 8(4):321–330
Tabur S, Oztuzcu S, Oguz E, Demiryu S, Dagli H, Alasehirli B et al (2016) Evidence for elevated (LIMK2 and CFL1) and suppressed (ICAM1, EZR, MAP2K2, and NOS3) gene expressions in metabolic syndrome. Endocrine 53(2):465–470
Ni C, Qiu H, Rezvan A, Kwon K, Nam D, Son DJ et al (2010) Discovery of novel mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow. Blood 116(15):E66–E73
Mullen RD, Colvin SC, Hunter CS, Savage JJ, Walvoord EC, Bhangoo APS et al (2007) Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development. Mol Cell Endocrinol 265:190–195
Ono R, Kaisho T, Tanaka T (2015) PDLIM1 inhibits NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm. Sci Rep 5:18327
Alnajar A, Nordhoff C, Schied T, Chiquet-ehrismann R, Loser K, Vogl T et al (2013) The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis. PLoS One 8(11):e81356
Muller JM, Metzger E, Greschik H (2002) The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. EMBO J 21(4):736–748
Caltagarone J, Hamilton RL, Murdoch G, Jing Z, DeFranco DB, Bowser R (2010) Paxillin and hydrogen peroxide-inducible clone 5 expression and distribution in control and Alzheimer disease hippocampi. J Neuropathol Exp Neurol 69(4):356–371
Ehaideb SN, Wignall EA, Kasuya J, Evans WH, Iyengar A, Koerselman HL et al (2016) Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans. Ann Clin Transl Neurol 3(9):695–707
Lanni C, Necchi D, Pinto A, Buoso E, Buizza L, Memo M et al (2013) Zyxin is a novel target for beta-amyloid peptide: characterization of its role in Alzheimer’s pathogenesis. J Neurochem 125(5):790–799
Matthews JM, Lester K, Joseph S, Curtis DJ (2013) LIM-domain-only proteins in cancer. Nat Rev Cancer 13(2):111–122
Li A, Ponten F, dos Remedios CG (2012) The interactome of LIM domain proteins: the contributions of LIM domain proteins to heart failure and heart development. Proteomics 12(2):203–225
Zheng Q, Zhao Y (2007) The diverse biofunctions of LIM domain proteins: determined by subcellular localization and protein-protein interaction. Biol Cell 99(9):489–502
Kadrmas JL, Beckerle MC (2004) The LIM domain: from the cytoskeleton to the nucleus. Nat Rev Mol Cell Biol 5(11):920–931
Stournaras C, Gravanis A, Margioris AN, Lang F (2014) The actin cytoskeleton in rapid steroid hormone actions. Cytoskeleton 71(5):285–293
Sever R, Glass CK (2013) Signaling by nuclear receptors. Cold Spring Harb Perspect Biol 5(3):1–4
Mullican SE, DiSpirito JR, Lazar MA (2013) The orphan nuclear receptors at their 25-year reunion. J Mol Endocrinol 51(3):T115–T140
Schock SC, Xu J, Duquette PM, Qin Z, Lewandowski AJ, Rai PS et al (2008) Rescue of neurons from ischemic injury by peroxisome proliferator-activated-receptor requires a novel essential cofactor LMO4. J Neurosci 28(47):12433–12444
Gu H, Liu T, Cai X, Tong Y, Li Y, Wang C et al (2015) Upregulated LMO1 in prostate cancer acts as a novel coactivator of the androgen receptor. Int J Oncol 47(6):2181–2187
Wang Y, Gilmore TD (2003) Zyxin and paxillin proteins: focal adhesion plaque LIM domain proteins go nuclear. Biochim Biophys Acta 1593(2–3):115–120
Rath N, Wang Z, Lu MM, Morrisey EE (2005) LMCD1/Dyxin is a novel transcriptional cofactor that restricts GATA6 function by inhibiting DNA binding. Mol Cell Biol 25(20):8864–8873
Chang C, Lin S, Su W, Ho C, Jou Y (2012) Somatic LMCD1 mutations promoted cell migration and tumor metastasis in hepatocellular carcinoma. Oncogene 31:2640–2652
Garvalov BK, Higgins TE, Sutherland JD, Zettl M, Scaplehorn N, Köcher T et al (2003) The conformational state of Tes regulates its zyxin-dependent recruitment to focal adhesions. J Cell Biol 161(1):33–39
Coutts AS, MacKenzie E, Griffith E, Black DM (2003) TES is a novel focal adhesion protein with a role in cell spreading. J Cell Sci 116(Pt 5):897–906
Nix DA, Beckerle MC (1997) Nuclear-cytoplasmic shuttling of the focal contact protein, zyxin: a potential mechanism for communication between sites of cell adhesion and the nucleus. J Cell Biol 138(5):1139–1147
Wang Y, Gilmore TD (2001) LIM domain protein Trip6 has a conserved nuclear export signal, nuclear targeting sequences, and multiple transactivation domains. Biochim Biophys Acta 1538(2–3):260–272
Kanungo J, Pratt SJ, Marie H, Longmore GD (2000) Ajuba, a cytosolic LIM protein, shuttles into the nucleus and affects embryonal cell proliferation and fate decisions. Mol Biol Cell 11(10):3299–3313
Petit MM, Fradelizi J, Golsteyn RM, Ayoubi TA, Menichi B, Louvard D et al (2000) LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity. Mol Biol Cell 11(1):117–129
Nishiya N, Sabe H, Nose K, Shibanuma M (1998) The LIM domains of hic-5 protein recognize specific DNA fragments in a zinc-dependent manner in vitro. Nucleic Acids Res 26(18):4267–4273
Campana WM, Myers RR, Rearden A (2003) Identification of PINCH in Schwann cells and DRG neurons: shuttling and signaling after nerve injury. Glia 41(3):213–223
Mihlan S, Reiß C, Thalheimer P, Herterich S, Gaetzner S, Kremerskothen J et al (2013) Nuclear import of LASP-1 is regulated by phosphorylation and dynamic protein–protein interactions. Oncogene 32(16):2107–2113
Yang N, Mizuno K (1999) Nuclear export of LIM-kinase 1, mediated by two leucine-rich nuclear export signals within the PDZ domain. Biochem J 338(Pt 3):793–798
Heitzer MD, DeFranco DB (2006) Hic-5, an adaptor-like nuclear receptor coactivator. Nucl Recept Signal 4:e019
Dong JM, Lau LS, Ng YW, Lim L, Manser E (2009) Paxillin nuclear-cytoplasmic localization is regulated by phosphorylation of the LD4 motif: evidence that nuclear paxillin promotes cell proliferation. Biochem J 418(1):173–184
Kaulfuss S, Herr AM, Büchner A, Hemmerlein B, Günthert AR, Burfeind P (2015) Leupaxin is expressed in mammary carcinoma and acts as a transcriptional activator of the estrogen receptor alpha. Int J Oncol 47(1):106–114
Ming S, Lee Y, Li HY, Kai E, Ng O, Man S et al (1999) Characterization of a brain-specific nuclear LIM domain protein (FHL1B) which is an alternatively spliced variant of FHL1. Gene 237:253–263
Goyal P, Pandey D, Siess W (2006) Phosphorylation-dependent regulation of unique nuclear and nucleolar localization signals of LIM kinase 2 in endothelial cells. J Biol Chem 281(35):25223–25230
Mori K, Asakawa M, Hayashi M, Imura M, Ohki T, Hirao E et al (2006) Oligomerizing potential of a focal adhesion LIM protein Hic-5 organizing a nuclear-cytoplasmic shuttling complex. J Biol Chem 281(31):22048–22061
Leach DA, Need EF, Trotta AP, Grubisha MJ, DeFranco DB, Buchanan G (2014) Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts. Mol Cell Endocrinol 384(1–2):185–199
Sen A, De Castro I, DeFranco DB, Deng FM, Melamed J, Kapur P et al (2012) Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. J Clin Investig 122(7):2469–2481
Youn H, Kim EJ, Um SJ (2013) Zyxin cooperates with PTOV1 to confer retinoic acid resistance by repressing RAR activity. Cancer Lett 331(2):192–199
Shibanuma M, Mori K, Kim-Kaneyama J, Nose K (2005) Involvement of FAK and PTP-PEST in the regulation of redox-sensitive nuclear-cytoplasmic shuttling of a LIM protein, Hic-5. Antioxid Redox Signal 7(2–3):335–347
Cattaruzza M, Lattrich C, Hecker M (2004) Focal adhesion protein zyxin is a mechanosensitive modulator of gene expression in vascular smooth muscle cells. Hypertension 43(4):726–730
McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D et al (2013) Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer Res 73(16):5066–5079
Kurakula K, Van Der Wal E, Geerts D, van Tiel CM, De Vries CJM (2011) FHL2 protein is a novel co-repressor of nuclear receptor Nur77. J Biol Chem 286(52):44336–44343
Muller J, Isele U, Metzger E, Rempel A, Moser M, Pscherer A et al (2000) FHL2, a novel tissue-specific coactivator of the androgen receptor. EMBO J 19(3):359–369
Kurakula K, Sommer D, Sokolovic M, Moerland PD, Scheij S, van Loenen PB et al (2015) LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis. Mol Cell Biol 35(1):52–62
Matulis CK, Mayo KE (2012) The LIM domain protein FHL2 interacts with the NR5A family of nuclear receptors and CREB to activate the inhibin-alpha subunit gene in ovarian granulosa cells. Mol Endocrinol 26(8):1278–1290
Xiong Z, Ding L, Sun J, Cao J, Lin J, Lu Z et al (2010) Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells. IUBMB Life 62(9):669–676
Ding L, Niu C, Zheng Y, Xiong Z, Liu Y, Lin J et al (2011) FHL1 interacts with oestrogen receptors and regulates breast cancer cell growth. J Cell Mol Med 15(1):72–85
Kobayashi S, Shibata H, Yokota K, Suda N, Murai A, Kurihara I et al (2004) FHL2, UBC9, and PIAS1 are novel estrogen receptor alpha-interacting proteins. Endocr Res 30(4):617–621
Sala S, Van Troys M, Medves S, Catillon M, Timmerman E, Staes A et al (2017) Expanding the interactome of TES by exploiting TES modules with different subcellular localizations. J Proteome Res 16(5):2054–2071
Wang X, Yang Y, Guo X, Sampson ER, Hsu C, Tsai M et al (2002) Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. J Biol Chem 277(18):15426–15431
Kaulfuss S, Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Neesen J et al (2008) Leupaxin, a novel coactivator of the androgen receptor, is expressed in prostate cancer and plays a role in adhesion and invasion of prostate carcinoma cells. Mol Endocrinol 22(7):1606–1621
Kasai M, Guerrero-santoro J, Friedman R, Leman ES, Getzenberg RH, Defranco DB (2003) The group 3 LIM domain protein paxillin potentiates androgen receptor transactivation in prostate cancer cell lines. Cancer Res 63(28):4927–4935
Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A et al (1999) Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem 274(12):8316–8321
Yang L, Guerrero J, Hong H, DeFranco DB, Stallcup MR (2000) Interaction of the tau2 transcriptional activation domain of glucocorticoid receptor with a novel steroid receptor coactivator, Hic-5, which localizes to both focal adhesions and the nuclear matrix. Mol Biol Cell 11(6):2007–2018
Chodankar R, Wu D, Gerke DS, Stallcup MR (2015) Selective coregulator function and restriction of steroid receptor chromatin occupancy by Hic-5. Mol Endocrinol 29(5):716–729
Drori S, Girnun GD, Tou L, Szwaya JD, Mueller E, Kia X et al (2005) Hic-5 regulates an epithelial program mediated by PPARγ. Genes Dev 19(3):362–375
Solomon JD, Heitzer MD, Liu TT, Beumer JH, Parise RA, Normolle DP et al (2014) VDR activity is differentially affected by Hic-5 in prostate cancer and stromal cells. Mol Cancer Res 12(8):1166–1180
Aghajanova L, Velarde MC, Giudice LC (2009) The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis. Endocrinology 150(8):3863–3870
Xie S, Ni J, Lee Y, Liu S, Li G, Shyr C et al (2011) Increased acetylation in the DNA-binding domain of TR4 nuclear receptor by the coregulator ARA55 leads to suppression of TR4 transactivation. J Biol Chem 286(24):21129–21136
He B, Minges JT, Lee LW, Wilson EM (2002) The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem 277(12):10226–10235
Guerrero-Santoro J, Yang L, Stallcup MR, DeFranco DB (2004) Distinct LIM domains of Hic-5/ARA55 are required for nuclear matrix targeting and glucocorticoid receptor binding and coactivation. J Cell Biochem 92(4):810–819
Li B, Trueb B (2001) Analysis of the alpha-Actinin/Zyxin interaction. J Biol Chem 276(36):33328–33335
Hou Z, Peng H, White DE, Negorev DG, Maul GG, Feng Y et al (2010) LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling. Proc Natl Acad Sci 107(7):2938–2943
Li Q, Peng H, Fan H, Zou X, Liu Q, Zhang Y et al (2016) The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction. Cell Death Differ 23(1):158–168
Lee JW, Choi HS, Gyuris J, Brent R, Moore DD (1995) Two classes of proteins dependent on either presence or absence of thyroid hormone for interaction with the thyroid-hormone receptor. Mol Endocrinol 9(2):243–254
Diefenbacher ME, Litfin M, Herrlich P, Kassel O (2010) The nuclear isoform of the LIM domain protein Trip6 integrates activating and repressing signals at the promoter-bound glucocorticoid receptor. Mol Cell Endocrinol 320(1–2):58–66
Fan H, Dong W, Li Q, Zou X, Zhang Y, Wang J et al (2015) Ajuba preferentially binds LXRα/RXRγ heterodimer to enhance LXR target gene expression in liver cells. Mol Endocrinol 29(11):1608–1618
Healy NC, O’Connor R (2009) Sequestration of PDLIM2 in the cytoplasm of monocytic/macrophage cells is associated with adhesion and increased nuclear activity of NF-kappaB. J Leukoc Biol 85(3):481–490
Sacchetti P, Carpentier R, Ségard P, Olivé-Cren C, Lefebvre P (2006) Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1. Nucleic Acids Res 34(19):5515–5527
Eom KS, Cheong JS, Lee SJ (2016) Structural analyses of zinc finger domains for specific interactions with DNA. J Microbiol Biotechnol 26(12):2019–2029
Matthews JM, Bhati M, Lehtomaki E, Mansfield RE, Cubeddu L, Mackay JP (2009) It takes two to tango: the structure and function of LIM, RING, PHD and MYND domains. Curr Pharm Des 15(31):3681–3696
Moes D, Gatti S, Hoffmann C, Dieterle M, Moreau F (2013) A LIM domain protein from tobacco involved in actin-bundling and histone gene transcription. Mol Plant 6(2):483–502
McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20(3):321–344
Heitzer MD, DeFranco DB (2006) Mechanism of action of Hic-5/androgen receptor activator 55, a LIM domain-containing nuclear receptor coactivator. Mol Endocrinol 20(1):56–64
Chodankar R, Wu DY, Schiller BJ, Yamamoto KR, Stallcup MR (2014) Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner. Proc Natl Acad Sci 111(11):4007–4012
Diefenbacher ME, Reich D, Dahley O, Kemler D, Litfin M, Herrlich P et al (2014) The LIM domain protein nTRIP6 recruits the mediator complex to AP-1-regulated promoters. PLoS One 9(5):e97549
Ciarlo JD, Flores AM, McHugh NG, Aneskievich BJ (2004) FHL2 expression in keratinocytes and transcriptional effect on PPARgamma/RXRalpha. J Dermatol Sci 35(1):61–63
Ishaq M, Lin BR, Bosche M, Zheng X, Yang J, Huang D et al (2011) LIM kinase 1- dependent cofilin 1 pathway and actin dynamics mediate nuclear retinoid receptor function in T lymphocytes. BMC Mol Biol 12(1):41
Mardilovich K, Gabrielsen M, McGarry L, Orange C, Patel R, Shanks E et al (2015) Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation. Mol Cancer Ther 14(1):246–258
Rahman MM, Miyamoto H, Lardy H, Chang C (2003) Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells. Proc Natl Acad Sci USA 100(9):5124–5129
Obrdlik A, Percipalle P (2011) The F-actin severing protein cofilin-1 is required for RNA polymerase II transcription elongation. Nucleus 2(1):72–79
Kristό I, Bajusz I, Bajusz C, Borkúti P, Vilmos P (2016) Actin, actin-binding proteins, and actin-related proteins in the nucleus. Histochem Cell Biol 145(4):373–388
Savoy RM, Chen L, Siddiqui S, Melgoza FU, Durbin-Johnson B, Drake C et al (2015) Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer. Endocr Relat Cancer 22(3):369–386
Zhao X, Khurana S, Charkraborty S, Tian Y, Sedor JR, Bruggman LA et al (2017) α actinin 4 (ACTN4) regulates glucocorticoid receptor-mediated transactivation and transrepression in podocytes. J Biol Chem 292(5):1637–1647
Ting HJ, Yeh S, Nishimura K, Chang C (2002) Supervillin associates with androgen receptor and modulates its transcriptional activity. Proc Natl Acad Sci 99(2):661–666
Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY et al (2003) Modulation of androgen receptor transactivation by gelsolin. Cancer Res 63(16):4888–4894
Dasgupta S, Lonard DM, O’Malley BW (2014) Nuclear receptor coactivators: master regulators of human health and disease. Annu Rev Med 65(1):279–292
Heitzer MD, DeFranco DB (2006) Hic-5/ARA55, a LIM domain-containing nuclear receptor coactivator expressed in prostate stromal cells. Cancer Res 66(14):7326–7333
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Sala, S., Ampe, C. An emerging link between LIM domain proteins and nuclear receptors. Cell. Mol. Life Sci. 75, 1959–1971 (2018). https://doi.org/10.1007/s00018-018-2774-3
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DOI: https://doi.org/10.1007/s00018-018-2774-3