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Gene Review

FHL2  -  four and a half LIM domains 2

Homo sapiens

Synonyms: AAG11, DRAL, FHL-2, Four and a half LIM domains protein 2, LIM domain protein DRAL, ...
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Disease relevance of FHL2


High impact information on FHL2

  • Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation [1].
  • The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus [7].
  • In addition, the transcription of the prostate-specific AR target gene probasin is coactivated by FHL2 [8].
  • FHL2 contains a strong, autonomous transactivation function and binds specifically to the AR in vitro and in vivo [8].
  • In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR, but not that of any other nuclear receptor [8].

Chemical compound and disease context of FHL2


Biological context of FHL2

  • Furthermore, we found that FHL2 significantly increased acetylation of beta-catenin by p300 in vivo [10].
  • The minimal binding sites for FHL2 and FHL3 on beta(1A)-chain overlap, whereas on alpha(7A) and alpha(7B) subunits they are situated adjacent [11].
  • Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET) [12].
  • However, overexpression of full-length FHL2 did not affect ERalpha-dependent transcriptional activities of a reporter containing 3 copies of estrogen response element in COS-1 cells [13].
  • Since tissue distribution of FHL2 was highly restricted to the heart, the function of FHL2 may be observed in a cell type- or promoter-specific manner [13].

Anatomical context of FHL2

  • In the adult, FHL2 is expressed in the myocardium of the heart and in the epithelial cells of the prostate, where it colocalizes with the AR in the nucleus [8].
  • Both FHL1 and FHL3 were expressed in a number of skeletal muscles while FHL2 was expressed at high levels in cardiac muscle [14].
  • We found that FHL2 and FHL3 were colocalized in the mitochondria of the C2C12 cells and FRET was observed by using an epi-fluorescent microscope equipped with an FRET specific filter set [12].
  • Northern blot analysis showed that FHL2 was strongly expressed in human osteoblasts [15].
  • When the human FHL2 cDNA probe was used to hybridize with poly-A RNA of various human tissues, a very strong signal could be seen in heart tissues, and only moderately low signals could be detected in placenta, skeletal muscle and ovary [16].

Associations of FHL2 with chemical compounds

  • The association of FHL2 or FHL3 with integrin receptors neither influences attachment of cells to different substrates nor changes their migration capacity [11].
  • FHL2 interacted with ERalpha in the presence of 17beta-estradiol, but not of tamoxifen or raloxifene in yeast [13].
  • We previously identified LSD1 and FHL2 as nuclear cofactors interacting specifically with the AR in prostate cells and showed that both stimulate androgen-dependent gene transcription [17].
  • Identification of the FHL2 Transcriptional Coactivator as a New Functional Target of the E7 Oncoprotein of Human Papillomavirus Type 16 [2].
  • In our study we investigated the association of pp125FAK, a cytoplasmic tyrosine kinase, involved in anchorage-independent growth of tumor cells, and the Four and a Half LIM domain (FHL) protein FHL2, which was recently shown to interact with integrins [5].

Physical interactions of FHL2


Regulatory relationships of FHL2

  • Thus, the ability of FHL2 to stimulate the trans-activating function of beta-catenin might be dependent on the promoter context [19].
  • BRCA1 enhanced FHL2-mediated transcriptional activity in transient transfections [3].
  • Overall, our findings indicate that FHL2 can also regulate p53 via a direct association with HIPK2 [20].
  • The functional interaction of HCF-1 with FHL2 supports a model in which site-specific proteolysis regulates the interaction of HCF-1 with protein partners and thus can modulate the activity of this coactivator [18].
  • This E4F1-FHL2 association occurs in the nuclear compartment and inhibits the capacity of E4F1 to block cell proliferation [21].

Other interactions of FHL2


Analytical, diagnostic and therapeutic context of FHL2


  1. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. Yang, Y., Hou, H., Haller, E.M., Nicosia, S.V., Bai, W. EMBO J. (2005) [Pubmed]
  2. Identification of the FHL2 Transcriptional Coactivator as a New Functional Target of the E7 Oncoprotein of Human Papillomavirus Type 16. Campo-Fern??ndez, B., Morandell, D., Santer, F.R., Zwerschke, W., Jansen-D??rr, P. J. Virol. (2007) [Pubmed]
  3. BRCA1 interacts with FHL2 and enhances FHL2 transactivation function. Yan, J., Zhu, J., Zhong, H., Lu, Q., Huang, C., Ye, Q. FEBS Lett. (2003) [Pubmed]
  4. Protein-protein interaction of FHL2, a LIM domain protein preferentially expressed in human heart, with hCDC47. Chan, K.K., Tsui, S.K., Ngai, S.M., Lee, S.M., Kotaka, M., Waye, M.M., Lee, C.Y., Fung, K.P. J. Cell. Biochem. (2000) [Pubmed]
  5. Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer. Gabriel, B., Mildenberger, S., Weisser, C.W., Metzger, E., Gitsch, G., Schüle, R., Müller, J.M. Anticancer Res. (2004) [Pubmed]
  6. Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. Wang, J., Yang, Y., Xia, H.H., Gu, Q., Lin, M.C., Jiang, B., Peng, Y., Li, G., An, X., Zhang, Y., Zhuang, Z., Zhang, Z., Kung, H.F., Wong, B.C. Gastroenterology (2007) [Pubmed]
  7. The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. Müller, J.M., Metzger, E., Greschik, H., Bosserhoff, A.K., Mercep, L., Buettner, R., Schüle, R. EMBO J. (2002) [Pubmed]
  8. FHL2, a novel tissue-specific coactivator of the androgen receptor. Müller, J.M., Isele, U., Metzger, E., Rempel, A., Moser, M., Pscherer, A., Breyer, T., Holubarsch, C., Buettner, R., Schüle, R. EMBO J. (2000) [Pubmed]
  9. Cardiac-specific LIM protein FHL2 modifies the hypertrophic response to beta-adrenergic stimulation. Kong, Y., Shelton, J.M., Rothermel, B., Li, X., Richardson, J.A., Bassel-Duby, R., Williams, R.S. Circulation (2001) [Pubmed]
  10. Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin. Labalette, C., Renard, C.A., Neuveut, C., Buendia, M.A., Wei, Y. Mol. Cell. Biol. (2004) [Pubmed]
  11. The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor. Samson, T., Smyth, N., Janetzky, S., Wendler, O., Müller, J.M., Schüle, R., von der Mark, H., von der Mark, K., Wixler, V. J. Biol. Chem. (2004) [Pubmed]
  12. Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET). Li, H.Y., Ng, E.K., Lee, S.M., Kotaka, M., Tsui, S.K., Lee, C.Y., Fung, K.P., Waye, M.M. J. Cell. Biochem. (2001) [Pubmed]
  13. FHL2, UBC9, and PIAS1 are novel estrogen receptor alpha-interacting proteins. Kobayashi, S., Shibata, H., Yokota, K., Suda, N., Murai, A., Kurihara, I., Saito, I., Saruta, T. Endocr. Res. (2004) [Pubmed]
  14. The LIM proteins FHL1 and FHL3 are expressed differently in skeletal muscle. Morgan, M.J., Madgwick, A.J. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  15. Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). Amaar, Y.G., Thompson, G.R., Linkhart, T.A., Chen, S.T., Baylink, D.J., Mohan, S. J. Biol. Chem. (2002) [Pubmed]
  16. Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart. Chan, K.K., Tsui, S.K., Lee, S.M., Luk, S.C., Liew, C.C., Fung, K.P., Waye, M.M., Lee, C.Y. Gene (1998) [Pubmed]
  17. Androgen Receptor Coactivators Lysine-Specific Histone Demethylase 1 and Four and a Half LIM Domain Protein 2 Predict Risk of Prostate Cancer Recurrence. Kahl, P., Gullotti, L., Heukamp, L.C., Wolf, S., Friedrichs, N., Vorreuther, R., Solleder, G., Bastian, P.J., Ellinger, J., Metzger, E., Sch??le, R., Buettner, R. Cancer Res. (2006) [Pubmed]
  18. Site-specific proteolysis of the transcriptional coactivator HCF-1 can regulate its interaction with protein cofactors. Vogel, J.L., Kristie, T.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Identification of the LIM protein FHL2 as a coactivator of beta-catenin. Wei, Y., Renard, C.A., Labalette, C., Wu, Y., Lévy, L., Neuveut, C., Prieur, X., Flajolet, M., Prigent, S., Buendia, M.A. J. Biol. Chem. (2003) [Pubmed]
  20. FHL2 mediates p53-induced transcriptional activation through a direct association with HIPK2. Lee, S.W., Kim, E.J., Um, S.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  21. The LIM-only protein FHL2 is a negative regulator of E4F1. Paul, C., Lacroix, M., Iankova, I., Julien, E., Schäfer, B.W., Labalette, C., Wei, Y., Le Cam, A., Le Cam, L., Sardet, C. Oncogene (2006) [Pubmed]
  22. Expression of androgen receptor coregulatory proteins in prostate cancer and stromal-cell culture models. Nessler-Menardi, C., Jotova, I., Culig, Z., Eder, I.E., Putz, T., Bartsch, G., Klocker, H. Prostate (2000) [Pubmed]
  23. Interaction of the heart-specific LIM domain protein, FHL2, with DNA-binding nuclear protein, hNP220. Ng, E.K., Chan, K.K., Wong, C.H., Tsui, S.K., Ngai, S.M., Lee, S.M., Kotaka, M., Lee, C.Y., Waye, M.M., Fung, K.P. J. Cell. Biochem. (2002) [Pubmed]
  24. Characterization of recombinant and natural forms of the human LIM domain-containing protein FHL2. El Mourabit, H., Müller, S., Tunggal, L., Paulsson, M., Aumailley, M. Protein Expr. Purif. (2003) [Pubmed]
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