nuclear receptor coactivator 2


Summary: A transcription factor that partners with ligand bound GLUCOCORTICOID RECEPTORS and ESTROGEN RECEPTORS to stimulate GENETIC TRANSCRIPTION. It plays an important role in FERTILITY as well as in METABOLISM of LIPIDS.

Top Publications

  1. Torchia J, Rose D, Inostroza J, Kamei Y, Westin S, Glass C, et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature. 1997;387:677-84 pubmed
  2. Ding X, Anderson C, Ma H, Hong H, Uht R, Kushner P, et al. Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol. 1998;12:302-13 pubmed
    ..In summary, GRIP1 and SRC-1 have overlapping NR-binding preferences, but specific NRs display both coactivator and NR Box preferences that may contribute to the specificity of hormonal responses. ..
  3. Chen S, Dowhan D, Hosking B, Muscat G. The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation. Genes Dev. 2000;14:1209-28 pubmed
  4. Li H, Gomes P, Chen J. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997;94:8479-84 pubmed
    ..Thus, RAC3 is a member of a growing coactivator network that should be useful as a tool for understanding hormone action and as a target for developing new therapeutic agents that can block hormone-dependent neoplasia. ..
  5. Reineke E, York B, Stashi E, Chen X, Tsimelzon A, Xu J, et al. SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart. PLoS ONE. 2012;7:e53395 pubmed publisher
  6. Lee Y, Koh S, Zhang X, Cheng X, Stallcup M. Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities. Mol Cell Biol. 2002;22:3621-32 pubmed
  7. Børud B, Hoang T, Bakke M, Jacob A, Lund J, Mellgren G. The nuclear receptor coactivators p300/CBP/cointegrator-associated protein (p/CIP) and transcription intermediary factor 2 (TIF2) differentially regulate PKA-stimulated transcriptional activity of steroidogenic factor 1. Mol Endocrinol. 2002;16:757-73 pubmed
    ..Thus, in contrast to the regulation of p/CIP and steroid receptor coactivator 1, we suggest that activation of PKA leads to selective down-regulation of TIF2 and subsequently repression of TIF2 coactivator function. ..
  8. Webb P, Nguyen P, Shinsako J, Anderson C, Feng W, Nguyen M, et al. Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol. 1998;12:1605-18 pubmed
    ..We propose that the ability of AF-1 and AF-2 to interact with separate surfaces of the same coactivator is important for the ability of these transactivation functions to synergize. ..
  9. He Y, Szapary D, Simons S. Modulation of induction properties of glucocorticoid receptor-agonist and -antagonist complexes by coactivators involves binding to receptors but is independent of ability of coactivators to augment transactivation. J Biol Chem. 2002;277:49256-66 pubmed

More Information


  1. Rogatsky I, Luecke H, Leitman D, Yamamoto K. Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. Proc Natl Acad Sci U S A. 2002;99:16701-6 pubmed
    ..Thus, in a single cell type, GR and GRIP1 conferred one mode of activation and two modes of repression by selectively engaging distinct surfaces of GRIP1 in a response element-specific manner. ..
  2. He B, Wilson E. Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs. Mol Cell Biol. 2003;23:2135-50 pubmed
    ..The data suggest a model whereby coactivator recruitment to the receptor AF2 surface is initiated by complementary charge interactions that reflect a reversal of the acidic activation domain-coactivator interaction model. ..
  3. Benecke A, Chambon P, Gronemeyer H. Synergy between estrogen receptor alpha activation functions AF1 and AF2 mediated by transcription intermediary factor TIF2. EMBO Rep. 2000;1:151-7 pubmed
    ..Thus, synergy between ER alpha AF1 and AF2 is a result of the cooperative recruitment of TIF2 and/or other members of the p160 coactivator family. ..
  4. Voegel J, Heine M, Zechel C, Chambon P, Gronemeyer H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996;15:3667-75 pubmed
    ..TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC-1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators. ..
  5. Chen D, Ma H, Hong H, Koh S, Huang S, Schurter B, et al. Regulation of transcription by a protein methyltransferase. Science. 1999;284:2174-7 pubmed
    ..Thus, coactivator-mediated methylation of proteins in the transcription machinery may contribute to transcriptional regulation. ..
  6. Lodrini M, Münz T, Coudevylle N, Griesinger C, Becker S, Pfitzner E. P160/SRC/NCoA coactivators form complexes via specific interaction of their PAS-B domain with the CID/AD1 domain. Nucleic Acids Res. 2008;36:1847-60 pubmed publisher
    ..Our study discloses a new, complementary mechanism for the current model of coactivator recruitment to target gene promoters. ..
  7. Fenne I, Hoang T, Hauglid M, Sagen J, Lien E, Mellgren G. Recruitment of coactivator glucocorticoid receptor interacting protein 1 to an estrogen receptor transcription complex is regulated by the 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase. Endocrinology. 2008;149:4336-45 pubmed publisher
    ..The initial stimulation of GRIP1 coactivator function is followed by an increased turnover and subsequent degradation of GRIP1 protein. ..
  8. Berrevoets C, Umar A, Trapman J, Brinkmann A. Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). Biochem J. 2004;379:731-8 pubmed
    ..These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR. ..
  9. Mark M, Yoshida Komiya H, Gehin M, Liao L, Tsai M, O Malley B, et al. Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction. Proc Natl Acad Sci U S A. 2004;101:4453-8 pubmed
  10. He Y, Simons S. STAMP, a novel predicted factor assisting TIF2 actions in glucocorticoid receptor-mediated induction and repression. Mol Cell Biol. 2007;27:1467-85 pubmed
    ..We suggest that STAMP is an important new, downstream component of GR action in both gene activation and gene repression. ..
  11. Wang D, Wang Q, Awasthi S, Simons S. Amino-terminal domain of TIF2 is involved in competing for corepressor binding to glucocorticoid and progesterone receptors. Biochemistry. 2007;46:8036-49 pubmed
    ..These results suggest that both N-terminal and middle sequences of TIF2 participate in competing with corepressor for regulating the gene transcriptional responses of GRs and PRs. ..
  12. Gregory C, Fei X, Ponguta L, He B, Bill H, French F, et al. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem. 2004;279:7119-30 pubmed
    ..The data indicate that EGF signaling through MAPK increases TIF2/GRIP1 coactivation of AR transactivation in recurrent prostate cancer. ..
  13. Hofman K, Swinnen J, Verhoeven G, Heyns W. Coactivation of an endogenous progesterone receptor by TIF2 in COS-7 cells. Biochem Biophys Res Commun. 2002;295:469-74 pubmed
  14. Xu J, Qiu Y, DeMayo F, Tsai S, Tsai M, O Malley B. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998;279:1922-5 pubmed
    ..The results indicate that SRC-1 mediates steroid hormone responses in vivo and that loss of its coactivator function results in partial resistance to hormone. ..
  15. McKenna N, Nawaz Z, Tsai S, Tsai M, O Malley B. Distinct steady-state nuclear receptor coregulator complexes exist in vivo. Proc Natl Acad Sci U S A. 1998;95:11697-702 pubmed
    ..Our results suggest that the assembly of large, modular transcriptional complexes by recruitment of distinct subclasses of preformed coregulator subcomplexes may be involved in transcriptional regulation by activated nuclear receptors. ..
  16. Mukherjee A, Soyal S, Fernandez Valdivia R, Gehin M, Chambon P, DeMayo F, et al. Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse. Mol Cell Biol. 2006;26:6571-83 pubmed
    ..We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function. ..
  17. Kindle K, Troke P, Collins H, Matsuda S, Bossi D, Bellodi C, et al. MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function. Mol Cell Biol. 2005;25:988-1002 pubmed
    ..In summary, our results indicate that disruption of the normal function of CBP and CBP-dependent activators is an important feature of MOZ-TIF2 action in AML. ..
  18. Hoang T, Fenne I, Cook C, Børud B, Bakke M, Lien E, et al. cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1. J Biol Chem. 2004;279:49120-30 pubmed
    ..Taken together, these data demonstrate that GRIP1 is ubiquitinated and degraded through activation of the PKA pathway. This may represent a novel regulatory mechanism whereby hormones down-regulate a nuclear receptor coactivator. ..
  19. Xu J, Li Q. Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrinol. 2003;17:1681-92 pubmed
    ..Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members. ..
  20. Beischlag T, Wang S, Rose D, Torchia J, Reisz Porszasz S, Muhammad K, et al. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Mol Cell Biol. 2002;22:4319-33 pubmed
    ..Taken together, these data support a role for the SRC family of transcriptional coactivators in TCDD-dependent gene regulation. ..
  21. Picard F, Gehin M, Annicotte J, Rocchi S, Champy M, O Malley B, et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002;111:931-41 pubmed
    ..Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain. These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism. ..
  22. Hudelist G, Czerwenka K, Kubista E, Marton E, Pischinger K, Singer C. Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. Breast Cancer Res Treat. 2003;78:193-204 pubmed
  23. Luo M, Simons S. Modulation of glucocorticoid receptor induction properties by cofactors in peripheral blood mononuclear cells. Hum Immunol. 2009;70:785-9 pubmed publisher
  24. Patchev A, Fischer D, Wolf S, Herkenham M, Götz F, Gehin M, et al. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J. 2007;21:231-8 pubmed
    ..Thus, hyperactivity of the hypothalamo-pituitary unit is ascribed to insidious adrenal insufficiency and impaired glucocorticoid feedback. ..
  25. Pathirage N, Di Nezza L, Salmonsen L, Jobling T, Simpson E, Clyne C. Expression of aromatase, estrogen receptors, and their coactivators in patients with endometrial cancer. Fertil Steril. 2006;86:469-72 pubmed
  26. Frigo D, Basu A, Nierth Simpson E, Weldon C, Dugan C, Elliott S, et al. p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1. Mol Endocrinol. 2006;20:971-83 pubmed
    ..The C terminus of GRIP1 was also demonstrated to contain a p38-responsive region. Taken together, these results indicate that p38 stimulates ER-mediated transcription by targeting the GRIP1 coactivator. ..
  27. Vivar O, Zhao X, Saunier E, Griffin C, Mayba O, Tagliaferri M, et al. Estrogen receptor beta binds to and regulates three distinct classes of target genes. J Biol Chem. 2010;285:22059-66 pubmed publisher
    ..Our findings indicate that the unliganded and liganded forms of ERbeta regulate three classes of genes by interacting with different transcription factors and coactivators. ..
  28. Belandia B, Parker M. Functional interaction between the p160 coactivator proteins and the transcriptional enhancer factor family of transcription factors. J Biol Chem. 2000;275:30801-5 pubmed
    ..These results suggest that the p160 proteins could be bona fide coactivators of the TEF family of transcription factors. ..
  29. Chopra A, Kommagani R, Saha P, Louet J, Salazar C, Song J, et al. Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption. Cell Metab. 2011;13:35-43 pubmed publisher
    ..Our results position the hepatic AMPK-SRC-2 axis as an energy rheostat, which upon cellular energy depletion resets whole-body energy by promoting absorption of dietary fuel...
  30. Ogawa H, Yu R, Haraguchi T, Hiraoka Y, Nakatani Y, Morohashi K, et al. Nuclear structure-associated TIF2 recruits glucocorticoid receptor and its target DNA. Biochem Biophys Res Commun. 2004;320:218-25 pubmed
    ..The TIF2 foci could recruit GR carrying a microinjected GR responsive element. We propose that TIF2 provides a nuclear compartment that allows the assembly of multi-protein complexes required for GR-mediated gene activation. ..
  31. Lopez G, Webb P, Shinsako J, Baxter J, Greene G, Kushner P. Titration by estrogen receptor activation function-2 of targets that are downstream from coactivators. Mol Endocrinol. 1999;13:897-909 pubmed
    ..The second factor would be needed by the TR for coactivator-mediated transcriptional stimulation. ..
  32. Kim J, Li H, Stallcup M. CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Mol Cell. 2003;12:1537-49 pubmed
    ..Thus, the N-terminal region of p160 coactivators contains an additional activation domain which contributes to coactivator function by recruitment of CoCoA. ..
  33. Jeong J, Kwak I, Lee K, White L, Wang X, Brunicardi F, et al. The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism. Mol Endocrinol. 2006;20:1138-52 pubmed
    ..This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated. ..
  34. Zou J, Zhong Z, Shi X, Tepper C, deVere White R, Kung H, et al. ACTR/AIB1/SRC-3 and androgen receptor control prostate cancer cell proliferation and tumor growth through direct control of cell cycle genes. Prostate. 2006;66:1474-86 pubmed
    ..These findings suggest that AR and ACTR may play important roles in androgen ablation resistance by controlling key cell cycle gene expression. ..
  35. Gehin M, Mark M, Dennefeld C, Dierich A, Gronemeyer H, Chambon P. The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Mol Cell Biol. 2002;22:5923-37 pubmed
    ..Thus, even though the three p160 coactivators exhibit strong sequence homology and similar activity in assays in vitro, they play distinct physiological roles in vivo, as their genetic eliminations result in distinct pathologies. ..
  36. Karmakar S, Gao T, Pace M, Oesterreich S, Smith C. Cooperative activation of cyclin D1 and progesterone receptor gene expression by the SRC-3 coactivator and SMRT corepressor. Mol Endocrinol. 2010;24:1187-202 pubmed publisher
  37. Voegel J, Heine M, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998;17:507-19 pubmed
  38. Mödder U, Monroe D, Fraser D, Spelsberg T, Rosen C, Gehin M, et al. Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2. J Biol Chem. 2009;284:18767-77 pubmed publisher
    ..Modulating SRC-2 action may, thus, represent a novel therapeutic target for osteoporosis. ..
  39. Shiau A, Barstad D, Loria P, Cheng L, Kushner P, Agard D, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95:927-37 pubmed
    ..These structures reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation. ..
  40. Ma H, Hong H, Huang S, Irvine R, Webb P, Kushner P, et al. Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol. 1999;19:6164-73 pubmed
  41. Modder U, Sanyal A, Kearns A, Sibonga J, Nishihara E, Xu J, et al. Effects of loss of steroid receptor coactivator-1 on the skeletal response to estrogen in mice. Endocrinology. 2004;145:913-21 pubmed
    ..These findings establish that, in mice, loss of SRC-1 leads to skeletal resistance to E predominantly in cancellous bone. ..
  42. Rogatsky I, Zarember K, Yamamoto K. Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J. 2001;20:6071-83 pubmed
    ..Cofactors such as GRIP1 probably contain distinct surfaces for activation and repression that function in a context-dependent manner. ..
  43. Jennings C, O Grady A, Cummins R, Murer B, Al Alawi M, Madden S, et al. Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma. J Thorac Oncol. 2012;7:243-8 pubmed publisher
    ..This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy. ..
  44. O Donnell K, Keng V, York B, Reineke E, Seo D, Fan D, et al. A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proc Natl Acad Sci U S A. 2012;109:E1377-86 pubmed publisher
    ..These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy. ..
  45. Hoang T, Fenne I, Madsen A, Bozickovic O, Johannessen M, Bergsvåg M, et al. cAMP response element-binding protein interacts with and stimulates the proteasomal degradation of the nuclear receptor coactivator GRIP1. Endocrinology. 2013;154:1513-27 pubmed publisher
    ..We propose that CREB mediates the PKA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1. ..
  46. Karmakar S, Foster E, Smith C. Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-alpha transcriptional activity. Endocrinology. 2009;150:1588-96 pubmed publisher
  47. Boorjian S, Heemers H, Frank I, Farmer S, Schmidt L, Sebo T, et al. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder. Endocr Relat Cancer. 2009;16:123-37 pubmed publisher
    ..03). Taken together, our data suggest an important role for AR-associated coactivators in UC and point toward differences in the regulation of AR activity between bladder and prostate cancer cells. ..
  48. Grenier J, Trousson A, Chauchereau A, Amazit L, Lamirand A, Leclerc P, et al. Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol. 2004;18:2866-79 pubmed
    ..We have shown that SRC-1 unexpectedly interacts with GR via its two nuclear receptor binding domains, thus providing a novel mechanism of GR signaling within the nervous system. ..
  49. Xu J, O Malley B. Molecular mechanisms and cellular biology of the steroid receptor coactivator (SRC) family in steroid receptor function. Rev Endocr Metab Disord. 2002;3:185-92 pubmed
  50. Wu H, Hamamori Y, Xu J, Chang S, Saluna T, Chang M, et al. Nuclear hormone receptor coregulator GRIP1 suppresses, whereas SRC1A and p/CIP coactivate, by domain-specific binding of MyoD. J Biol Chem. 2005;280:3129-37 pubmed
    ..This suggests that competition by GRIP1 for SRC1A, p/CIP, and p300 binding sites on a transcription factor may regulate the activity of the factor. ..
  51. Anzick S, Kononen J, Walker R, Azorsa D, Tanner M, Guan X, et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997;277:965-8 pubmed
    ..These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers. ..
  52. York B, Sagen J, Tsimelzon A, Louet J, Chopra A, Reineke E, et al. Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family. Mol Endocrinol. 2013;27:366-80 pubmed publisher
    ..Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators. ..