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Gene Review

FHL3  -  four and a half LIM domains 3

Homo sapiens

Synonyms: FHL-3, Four and a half LIM domains protein 3, SLIM-2, SLIM2, Skeletal muscle LIM-protein 2
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Disease relevance of FHL3


High impact information on FHL3

  • On target interaction and degranulation, FHL3 NK cells displayed low levels of surface CD107a staining, in contrast to healthy control subjects or perforin-deficient NK cells [4].
  • Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations [1].
  • These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts [1].
  • The C-subunit of NFY was demonstrated to form a ternary complex with MZF-1/FHL3 and interact with a beta-chain gene region including the element in the fourth intron [5].
  • We also found that GM-CSF induced expression of MZF-1 and nuclear translocation of FHL3 [5].

Biological context of FHL3

  • 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 [6].
  • Localisation of FHL3 to human chromosome 1 placed this gene in the proximity of, but not overlapping with, alleles associated with muscle diseases [7].
  • Deletion and point mutation studies indicated that the second LIM domain of FHL3 was essential for this interaction [8].
  • In this report, FHL3 (human four-and-a-half LIM-only protein 3) is shown to interact with human phosphatase CDC25B, a cell cycle regulator involved in the control of G2/M [8].
  • Green fluorescent protein (GFP) was used to tag FHL3 in order to study its distribution during myogenesis [9].

Anatomical context of FHL3

  • Both FHL1 and FHL3 were expressed in a number of skeletal muscles while FHL2 was expressed at high levels in cardiac muscle [7].
  • FHL3 expresses predominantly in human skeletal muscle [9].
  • Our result shows that FHL3 was localized in the focal adhesions and nucleus of the cells [9].
  • 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 [9].
  • Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission [1].

Associations of FHL3 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 [6].

Physical interactions of FHL3


Regulatory relationships of FHL3

  • Overexpression of FHL3 in KU812 cells suppressed the beta-chain promoter activity through the element in the fourth intron in an MZF-1-dependent manner [11].

Other interactions of FHL3

  • Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET) [9].
  • Furthermore, results from pull-down assays and gel-filtration chromatography employing nuclear extracts indicated that MZF-1 and FHL3 formed a complex of high molecular mass with some additional proteins in the nucleus [11].
  • BACKGROUND: Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible [2].

Analytical, diagnostic and therapeutic context of FHL3


  1. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Ishii, E., Ueda, I., Shirakawa, R., Yamamoto, K., Horiuchi, H., Ohga, S., Furuno, K., Morimoto, A., Imayoshi, M., Ogata, Y., Zaitsu, M., Sako, M., Koike, K., Sakata, A., Takada, H., Hara, T., Imashuku, S., Sasazuki, T., Yasukawa, M. Blood (2005) [Pubmed]
  2. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Ueda, I., Ishii, E., Morimoto, A., Ohga, S., Sako, M., Imashuku, S. Pediatric blood & cancer. (2006) [Pubmed]
  3. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J.C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L.D., Griffiths, G.M., Aric??, M. J. Med. Genet. (2006) [Pubmed]
  4. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Marcenaro, S., Gallo, F., Martini, S., Santoro, A., Griffiths, G.M., Aricó, M., Moretta, L., Pende, D. Blood (2006) [Pubmed]
  5. Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor beta-Chain Gene Induced by GM-CSF. Takahashi, K., Hayashi, N., Kaminogawa, S., Ra, C. J. Immunol. (2006) [Pubmed]
  6. 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]
  7. The LIM proteins FHL1 and FHL3 are expressed differently in skeletal muscle. Morgan, M.J., Madgwick, A.J. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  8. LIM-only protein FHL3 interacts with CDC25B2 phosphatase. Mils, V., Lee, S.M., Joly, W., Hang, E.W., Baldin, V., Waye, M.M., Ducommun, B., Tsui, S.K. Exp. Cell Res. (2003) [Pubmed]
  9. 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]
  10. The LIM protein FHL3 binds basic Krüppel-like factor/Krüppel-like factor 3 and its co-repressor C-terminal-binding protein 2. Turner, J., Nicholas, H., Bishop, D., Matthews, J.M., Crossley, M. J. Biol. Chem. (2003) [Pubmed]
  11. FHL3 negatively regulates human high-affinity IgE receptor beta-chain gene expression by acting as a transcriptional co-repressor of MZF-1. Takahashi, K., Matsumoto, C., Ra, C. Biochem. J. (2005) [Pubmed]
  12. Chromosomal mapping of a skeletal muscle specific LIM-only protein FHL3 to the distal end of the short arm of human chromosome 1. Lee, S.M., Tsui, S.K., Chan, K.K., Kotaka, M., Li, H.Y., Chim, S.S., Waye, M.M., Fung, K.P., Lee, C.Y. Somat. Cell Mol. Genet. (1998) [Pubmed]
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