FHL2
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Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene.[5] LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.[6]
Function
FHL-2 is thought to have a role in the assembly of extracellular membranes and may function as a link between
Family
The Four-and-a-half LIM (FHL)-only protein subfamily is one of the members of the LIM-only protein family. Protein members within the group might be originated from a common ancestor and share a high degree of similarity in their amino acid sequence.[7] These proteins are defined by the presence of the four and a half cysteine-rich LIM homeodomain with the half-domain always located in its N-terminus.[8] The name LIM was derived from the first letter of the transcription factors LIN-11, ISL-1 and MEC-3, from which the domain was originally characterized.[9] No direct interactions between LIM domain and DNA have been reported. Instead, extensive evidence points towards the functional role of FHL2 in supporting protein-protein interactions of LIM-containing proteins and its binding partners.[10][11][12][13] Thus far, five members have been categorized into the FHL subfamily, which are FHL1, FHL2, FHL3, FHL4 and activator of CREM in testis (ACT) in human.[14] FHL1, FHL2 and FHL3 are predominantly expressed in muscle,[15][16] while FHL4 and FHL5 are expressed exclusively in testis.[17]
Gene
FHL2 is the best studied member within the subfamily. The protein is encoded by the fhl2 gene being mapped in the region of human chromosome 2q12-q14.
Tissue distribution
FHL2 exhibits diverse expression patterns in a cell/tissue-specific manner, which has been found in liver, kidney, lung, ovary, pancreas, prostate, stomach, colon, cortex, and in particular, the heart. However, its expression in some immune-related tissues like the spleen,
Regulation of expression
Different transcription factors that have been reported responsible for the regulation of fhl2 expression include the well-known tumor suppressor protein p53,[19][23] serum response factor (SRF),[24][25] specificity protein 1 (Sp1).[26] the pleiotropic factor IL-1β,[27] MEF-2,[14] and activator protein-1 (AP-1).[28] Apart from being regulated by different transcription factors, FHL2 is itself involved extensively in regulating the expression of other genes. FHL2 exerts its transcriptional regulatory effects by functioning as an adaptor protein interacting indirectly with the targeted genes. In fact, LIM domain is a platform for the formation of multimeric protein complexes.[29] Therefore, FHL2 can contribute to human carcinogenesis by interacting with transcription factors of cancer-related genes and modulates the signaling pathways underlying the expression of these genes. Different types of cancer are associated with FHL2 which act either as the cancer suppressor or inducer, for example in breast cancer, gastrointestinal (GI) cancers, liver cancer and prostate cancer.
Clinical significance
The expression and functions of FHL2 varies greatly depending on the cancer types. It appeared that phenomenon is highly related to the differential mechanistic transcriptional regulations of FHL2 in the various types of cancer. However, the participation of fhl2 mutations and the
Phosphorylation of FHL-2 protein has no significant effects on FHL2 functioning both in vitro and in vivo.[31][32] Provided that the existence of posttranscriptional modifications on FHL2 other than phosphorylation is still unclear and FHL2 functions almost exclusively through protein-protein interactions, research works in this direction is still interested. In particular, the mechanisms underpinning the subcellular localization of FHL2 should be focused. FHL2 can traffic freely between nuclear and the different cellular compartments.[14] It also interacts with other proteinaceous binding partners belonging to different functional classes including, but not limited to, transcription factors and signal transducers.[10][16][33][34] Therefore, FHL2 translocation could be important in regulating the different molecular signaling pathways which modify carcinogenesis, for example, nuclear translocation of FHL2 is related to aggressiveness and recurrence of prostate cancer[35] Similar evidence also has been identified in experiment using A7FIL+ cells and NIH 3T3 cell line as the disease model.[20][36][37]
Breast cancer
The FHL2 protein interacts with the breast cancer type 1 susceptibility gene (BRCA1) which enhances the transactivation of BRCA1.[38] In addition, intratumoral FHL2 level was one of the factors determining the worse survival of breast cancer patients[39]
Gastrointestinal cancer
FHL2 is related to
Liver cancer
In the most common form liver cancer, the hepatocellular carcinoma (HCC), FHL2 is always downregulated in the clinical samples.[19] Therefore, fhl2 is exhibiting a tumor-suppressive effect on HCC. Similar to p53, overexpression of FHL2 inhibit the proliferative activity of the HCC Hep3B cell line by decreasing its cyclin D1 expression and increasing P21 and P27 expression supporting the time-dependent cellular repair process.[44] Of note, a database of FHL2-regulated genes in murine liver has recently been established by using microarray and bioinformatics analysis, which provide useful information concerning most of the pathways and new genes related to FHL2.[45]
Prostate cancer
The molecular communication between
Interactions
FHL2 has been shown to
Notes
Wikidata Q38554494 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000115641 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000008136 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ a b "Entrez Gene: FHL2 four and a half LIM domains 2".
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Further reading
- Genini M, Schwalbe P, Scholl FA, Remppis A, Mattei MG, Schäfer BW (1997). "Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma". DNA Cell Biol. 16 (4): 433–42. PMID 9150430.
- Chan KK, Tsui SK, Lee SM, Luk SC, Liew CC, Fung KP, Waye MM, Lee CY (1998). "Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart". Gene. 210 (2): 345–50. PMID 9573400.
- Chan KK, Tsui SK, Ngai SM, Lee SM, Kotaka M, Waye MM, Lee CY, Fung KP (2000). "Protein-protein interaction of FHL2, a LIM domain protein preferentially expressed in human heart, with hCDC47". J. Cell. Biochem. 76 (3): 499–508. S2CID 30843438.
- Müller JM, Isele U, Metzger E, Rempel A, Moser M, Pscherer A, Breyer T, Holubarsch C, Buettner R, Schüle R (2000). "FHL2, a novel tissue-specific coactivator of the androgen receptor". EMBO J. 19 (3): 359–69. PMID 10654935.
- Wixler V, Geerts D, Laplantine E, Westhoff D, Smyth N, Aumailley M, Sonnenberg A, Paulsson M (2000). "The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes". J. Biol. Chem. 275 (43): 33669–78. PMID 10906324.
- Tanahashi H, Tabira T (2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Hum. Mol. Genet. 9 (15): 2281–9. PMID 11001931.
- Fimia GM, De Cesare D, Sassone-Corsi P (2000). "A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM". Mol. Cell. Biol. 20 (22): 8613–22. PMID 11046156.
- Scholl FA, McLoughlin P, Ehler E, de Giovanni C, Schäfer BW (2000). "DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis". J. Cell Biol. 151 (3): 495–506. PMID 11062252.
- Li HY, Kotaka M, Kostin S, Lee SM, Kok LD, Chan KK, Tsui SK, Schaper J, Zimmermann R, Lee CY, Fung KP, Waye MM (2001). "Translocation of a human focal adhesion LIM-only protein, FHL2, during myofibrillogenesis and identification of LIM2 as the principal determinants of FHL2 focal adhesion localization". Cell Motil. Cytoskeleton. 48 (1): 11–23. PMID 11124707.
- Li HY, Ng EK, Lee SM, Kotaka M, Tsui SK, Lee CY, Fung KP, Waye MM (2001). "Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET)". J. Cell. Biochem. 80 (3): 293–303. S2CID 36346381.
- Dye BT, Patton JG (2001). "An RNA recognition motif (RRM) is required for the localization of PTB-associated splicing factor (PSF) to subnuclear speckles". Exp. Cell Res. 263 (1): 131–44. PMID 11161712.
- Ng EK, Chan KK, Wong CH, Tsui SK, Ngai SM, Lee SM, Kotaka M, Lee CY, Waye MM, Fung KP (2002). "Interaction of the heart-specific LIM domain protein, FHL2, with DNA-binding nuclear protein, hNP220". J. Cell. Biochem. 84 (3): 556–66. S2CID 2842198.
- Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S (2002). "Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2)". J. Biol. Chem. 277 (14): 12053–60. PMID 11821401.
- Stilo R, Leonardi A, Formisano L, Di Jeso B, Vito P, Liguoro D (2002). "TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of NF-kappaB activation". FEBS Lett. 521 (1–3): 165–9. S2CID 21781671.
- McLoughlin P, Ehler E, Carlile G, Licht JD, Schäfer BW (2002). "The LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the promyelocytic leukemia zinc finger protein". J. Biol. Chem. 277 (40): 37045–53. PMID 12145280.
- Jiang LQ, Wen SJ, Wang HY, Chen LY (2002). "Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system". Hypertens. Res. 25 (4): 647–52. PMID 12358155.
- Schlisio S, Halperin T, Vidal M, Nevins JR (2002). "Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function". EMBO J. 21 (21): 5775–86. PMID 12411495.
- Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (2002). "Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2". J. Cell Sci. 115 (Pt 24): 4925–36. PMID 12432079.
- Wei Y, Renard CA, Labalette C, Wu Y, Lévy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA (2003). "Identification of the LIM protein FHL2 as a coactivator of beta-catenin". J. Biol. Chem. 278 (7): 5188–94. PMID 12466281.
External links
- FHL2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: Q14192 (Four and a half LIM domains protein 2) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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