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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LIM domain-containing proteins play critical roles in vertebrate development and cellular differentiation. Recently, four members of the four and one-half LIM protein (FHL) family have been identified and cloned. One of these, FHL2, is expressed in a restricted manner in the cardiovascular system throughout development into adulthood, suggesting that FHL2 may play an important role in cardiovascular development and function. Here we describe the generation and analysis of mice carrying a null mutation of the FHL2 gene. FHL2-deficient mice are viable and maintain normal cardiac function both before and after acute mechanical stress induced by aortic constriction. These data suggest that FHL2 is not essential for cardiac development and function.
Mol Cell Biol 2000 Oct
PMID:FHL2 (SLIM3) is not essential for cardiac development and function. 1100 43

The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.
Mol Cell Biol 2004 Feb
PMID:Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. 1472 55

The basic helix-loop-helix (bHLH) factor Hand1 plays an essential role in cardiac morphogenesis, and yet its precise function remains unknown. Protein-protein interactions involving Hand1 provide a means of determining how Hand1-induced gene expression in the developing heart might be regulated. Hand1 is known to form either heterodimers with near-ubiquitous E-factors and other lineage-restricted class B bHLH proteins or homodimers with itself in vitro. To date, there have been no reported Hand1 protein interactions involving non-bHLH proteins. Heterodimer-versus-homodimer choice is mediated by the phosphorylation status of Hand1; however, little is known about the in vivo function of these dimers or, importantly, how they are regulated. In an effort to understand how Hand1 activity in the heart might be regulated postdimerization, we have investigated tertiary Hand1-protein interactions with non-bHLH factors. We describe a novel interaction of Hand1 with the LIM domain protein FHL2, a known transcriptional coactivator and corepressor expressed in the developing cardiovascular system. FHL2 interacts with Hand1 via the bHLH domain and is able to repress Hand1/E12 heterodimer-induced transcription but has no effect on Hand1/Hand1 homodimer activity. This effect of FHL2 is not mediated either at the level of dimerization or via an effect of Hand1/E12 DNA binding. In summary, our data describe a novel differential regulation of Hand1 heterodimers versus homodimers by association of the cofactor FHL2 and provide insight into the potential for a tertiary level of control of Hand1 activity in the developing heart.
Mol Cell Biol 2004 Nov
PMID:Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2. 1550 87

Transcriptional activation of gene expression by Wnt signaling is driven by the association of beta-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate beta-catenin transactivating activity and that beta-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced beta-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and beta-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and beta-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2(-/-) embryo fibroblasts, the transactivation activity of beta-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the beta-catenin/TCF complex in FHL2(-/-) cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on beta-catenin. Furthermore, we found that FHL2 significantly increased acetylation of beta-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and beta-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF.
Mol Cell Biol 2004 Dec
PMID:Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin. 1557 74

RhoA signaling regulates the activity of the transcription factor SRF (serum response factor) during muscle differentiation. How RhoA signaling is integrated at SRF target promoters to achieve muscle-lineage-specific expression is largely unknown. Using large-scale expression profiling combined with bioinformatic and biochemical approaches, we identified several SRF target genes, including Fhl2, encoding a transcriptional cofactor that is highly expressed in the heart. SRF binds the Fhl2 promoter in vivo and regulates Fhl2 expression in response to RhoA activation. FHL2 protein and SRF interact physically, and FHL2 binds the promoters of SRF-responsive smooth muscle (SM) genes, but not the promoters of immediate-early genes (IEGs), in response to RhoA. FHL2 antagonizes induction of SM genes, but not IEGs or cardiac genes, by competing with the coactivator MAL/MRTF-A for SRF binding. Our findings identify an autoregulatory mechanism to selectively regulate subsets of RhoA-activated SRF target genes.
Mol Cell 2004 Dec 22
PMID:The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. 1561 Jul 31

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.
Hum Mol Genet 2005 Mar 15
PMID:Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. 1570 95

Numerous cellular processes require the concerted action of multiple proteins that assemble in functional complexes. Protein-protein interaction domains allow specific proteins to combine with certain partners. Specificity of protein-protein association can be obtained by an interaction code predicted by conserved amino acid sequences. One of the protein-protein interaction motifs is the LIM domain, a conserved cysteine-rich module present in more than 100 different human proteins. The human four-and-a-half-LIM-only protein family consists of the members FHL1, FHL2, FHL3, FHL4 and ACT. They are expressed in a cell- and tissue-specific manner and participate in various cellular processes, including regulation of cell survival, transcription and signal transduction. Here, we review the current knowledge of the best-studied member of this family, FHL2. We describe the transcription regulation, the expression profile, the interaction partners, the subcellular localization, the biological functions and discuss the possible involvement of FHL2 in human diseases.
Cell Mol Life Sci 2006 Feb
PMID:The multifunctional roles of the four-and-a-half-LIM only protein FHL2. 1638 49

In osteoarthritis (OA), cartilage destruction is associated not only with an imbalance of anabolic and catabolic processes but also with alterations of the cytoskeletal organization in chondrocytes, although their pathogenetic origin is largely unknown so far. Therefore, we have studied possible effects of the proinflammatory cytokine IL-1beta on components of the cytoskeleton in OA chondrocytes on gene expression level. Using a whole genome array, we found that IL-1beta is involved in the regulation of many cytoskeleton-related genes. Apart from well-known cytoskeletal components, the expression and regulation of four genes coding for LIM proteins were shown. These four genes were previously undescribed in the chondrocyte context. Quantitative PCR analysis confirmed significant downregulation of Fhl1, Fhl2, Lasp1, and Pdlim1 as well as Tubb and Vim by IL-1beta. Inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580 counteracted the influence of IL-1beta on Fhl2 and Tubb expression, indicating partial involvement of this signaling pathway. Downregulation of the LIM-only protein FHL2 was confirmed additionally on the protein level. In agreement with these results, IL-1beta induced changes in the morphology of chondrocytes, the organization of the cytoskeleton, and the cellular distribution of FHL2. We conclude that L-1beta is involved in the regulation of various cytoskeletal components in human chondrocytes including the multifunctional protein FHL2. This might be relevant for the pathogenesis of OA.
Mol Med
PMID:IL-1beta regulates FHL2 and other cytoskeleton-related genes in human chondrocytes. 1822 50

Aberrant coregulator expression that occurs during prostate cancer (PCa) progression correlates with poor prognosis and aggressive disease. This has been attributed to the ability to regulate androgen receptor-mediated transcription. We have shown previously that the androgenic milieu regulates the expression of the coactivators p300 and FHL2, with severe consequences for PCa cell proliferation and androgen receptor transcriptional activity. To determine the extent of androgen dependency of coregulator genes, we designed a cDNA-mediated annealing, selection, extension, and ligation RNA profiling array that probes the expression of 186 coregulators. Using this assay, we demonstrated androgen control over approximately 30% of coregulator genes in PCa cells. For a subset of 15 functionally diverse coregulators, androgen regulation was confirmed using real-time RT-PCR and immunoblotting. The extent, dose dependency, and kinetics by which androgens affect coregulator expression differed widely, indicating diverse molecular mechanisms underlying these effects. Moreover, differences in coregulator expression were observed between isogenic androgen-dependent and castration-recurrent PCa cells. Small interfering RNA-mediated changes in coregulator expression had profound effects on cell proliferation, which were most pronounced in castration-recurrent cells. Taken together, our integrated approach combining expression profiling, characterization of androgen-dependent coregulator expression, and validation of the importance of altered coregulator expression for cell proliferation identified several potential novel therapeutic targets for PCa treatment.
Mol Endocrinol 2009 Apr
PMID:Androgen modulation of coregulator expression in prostate cancer cells. 1916 47

Aryl hydrocarbon receptor (AhR) ligands modulate androgen receptor (AR) signaling in prostate cancer cells through partially defined mechanisms. Furthermore, these facilitatory and inhibitory effects of AhR on AR signaling appear to be cell or context specific. In the present study we demonstrate that both AhR and AhR-nuclear translocator (ARNT) interact with AR. AhR but not ARNT enhanced the AR-transcriptional activity which was independent of exogenous AhR ligand treatment (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). We then tested if coactivators common to both receptors alter the facilitatory effect of AhR on AR activity. NcoA4 overexpression did not alter the AhR facilitatory effect on AR, whereas SRC1 overexpression further enhanced the effect. In contrast, FHL2 overexpression blocked the facilitatory effect of AhR. In the presence of exogenous FHL2 expression, AhR repressed AR activity, whereas at low endogenous levels of FHL2 expression, AhR overexpression enhanced AR activity. At high FHL2 expression levels, TCDD treatment decreased AR activity and this effect was reversed by AhR overexpression. These findings demonstrate that AhR modulation of AR activity is differentially altered by the level of FHL2 and AhR present in the cell.
J Steroid Biochem Mol Biol 2010 Jan
PMID:Four and a half LIM domain 2 alters the impact of aryl hydrocarbon receptor on androgen receptor transcriptional activity. 1981 66


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