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]
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]
FHL-2 is thought to have a role in the assembly of extracellular membranes and may function as a link between presenilin-2 and an intracellular signaling pathway. [6]
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]
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. [18] Two alternative promoters, 1a and 1b, as well as 5 transcript variants of fhl2 have been reported. [19]
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, thymus and blood leukocytes has not been documented. [20] Intriguingly, the FHL2 expression and function varies significantly between different types of cancer. [19] [21] [22] [23] Such discrepancies are most likely due to the existence of the wide variety of transcription factors governing FHL2 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.
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 posttranslational modifications of fhl2 in carcinogenesis cannot be ignored. In fact, functional mutation of fhl2 has been identified in a patient with familial dilated cardiomyopathy (DCM) and is associated with its pathogenesis. [30] This implied that fhl2 mutation may also profoundly affect the diverse cancer progressions. However, records describing the effects of fhl2 mutations on carcinogenesis are scarce.
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]
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]
FHL2 is related to gastrointestinal cancers and in particular, colon cancer. Fhl2 demonstrates an oncogenic property in colon cancer which induces the differentiation of some in vitro colon cancer models. [21] [40] [41] FHL2 is as well crucial to colon cancer cells invasion, migration and adhesion to extracellular matrix. The expression of FHL2 is positively regulated by transforming growth factor beta 1 (TGF-β1) stimulations which induces epithelial-mesenchymal transition (EMT) and endows cancer cells with metastatic properties. The TGF-β1-midiated alternation of FHL2 expression level might therefore trigger colon cell invasion. Besides, the subcellular localization of FHL2 can be modulated by TGF-β1 in sporadic colon cancer which resulted in the polymerization of alpha smooth muscle actin (α-SMA). [42] This process induces the fibroblast to take up a myofibroblast phenotype and contributes to cancer invasion. FHL2 can also induce EMT and cancer cell migration by affecting the structural integrity of membrane-associated E-cadherin-β-catenin complex. [43]
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]
The molecular communication between androgen receptor (AR) and FHL2 is linked to the disease development of prostate cancer such as aggressiveness and biochemical recurrence (i.e., rise in circulatory prostate-specific antigen (PSA) levels after surgical or radiography treatment) [46] [47] FHL2 expression is profoundly initiated by androgen through the mediation of serum response factor (SFR) and the RhoA / actin / megakaryocytic acute leukemia (MAL) signaling axis functioning upstream of SRF. [46] [48] On the other hand, FHL2 is the coactivator of AR and is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor (AhR) imposing AR activity with as yet unknown mechanisms. [49] Calpain cleavage of cytoskeletal protein filamin which is increased in prostate cancer could induce the nuclear translocation of FHL2, and this subsequently increase AR coactivation. [37]
FHL2 has been shown to interact with:
 | The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Cyanne Ye Cao; Simon Wing-Fai Mok; Vincent Wing-Sang Cheng; Stephen Kwok-Wing Tsui (26 July 2015). "The FHL2 regulation in the transcriptional circuitry of human cancers". Gene . Gene Wiki Review Series. 572 (1): 1–7. doi:10.1016/J.GENE.2015.07.043. ISSN 0378-1119. PMC 5975090 . PMID 26211626. Wikidata Q38554494. |
The androgen receptor (AR), also known as NR3C4, is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.
The nuclear receptor coactivator 1 (NCOA1) is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA1, in turn, acylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA1 assists nuclear receptors in the upregulation of DNA expression.
The nuclear receptor coactivator 2 also known as NCoA-2 is a protein that in humans is encoded by the NCOA2 gene. NCoA-2 is also frequently called glucocorticoid receptor-interacting protein 1 (GRIP1), steroid receptor coactivator-2 (SRC-2), or transcriptional mediators/intermediary factor 2 (TIF2).
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.
Transforming growth factor beta-1-induced transcript 1 protein is a protein that in humans is encoded by the TGFB1I1 gene. Often put together with and studied alongside TGFB1I1 is the mouse homologue HIC-5. As the name suggests, TGFB1I1 is an induced form of the larger family of TGFB1. Studies suggest TGFB1I1 plays a role in processes of cell growth, proliferation, migration, differentiation and senescence. TGFB1I1 is most localized at focal adhesion complexes of cells, although it may be found active in the cytosol, nucleus and cell membrane as well.
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.
Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the NRIP1 gene.
Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the NCOA4 gene. It plays an important role in ferritinophagy, acting as a cargo receptor, binding to the ferritin heavy chain and latching on to ATG8 on the surface of the autophagosome.
Serum response factor, also known as SRF, is a transcription factor protein.
E3 SUMO-protein ligase PIAS1 is an enzyme that in humans is encoded by the PIAS1 gene.
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.
Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein.
Protein UXT also known as androgen receptor trapped clone 27 (ART-27) protein is a protein that in humans is encoded by the UXT gene.
Glutamate receptor-interacting protein 1 is a protein that in humans is encoded by the GRIP1 gene.
Four and a half LIM domains protein 3 is a protein that in humans is encoded by the FHL3 gene.
E3 ubiquitin-protein ligase RNF14 is an enzyme that in humans is encoded by the RNF14 gene.
Melanoma-associated antigen 11 is a protein that in humans is encoded by the MAGEA11 gene. It is also involved in the androgen and progesterone receptor signaling pathways.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
PDB gallery | |
|---|---|
|
