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FLASH GENE

Symbol

FHL2

contributors: mct/pgu - updated : 04-10-2023

HGNC name	four and a half LIM domains 2
HGNC id	3703

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMD1H cardiomyopathy, dilated 1H
Location	2q12.2      Physical location : 105.977.284 - 106.055.230
Synonym name	down-regulated in rhabdomyosarcoma LIM protein
	skeletal muscle lim protein 3
	aging associated gene 11
	LIM domain protein DRAL
Synonym symbol(s)	DRAL, SLIM3, AAG11, FHL-2

DNA

TYPE	functioning gene
STRUCTURE	80.82 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	a functional promoter region upstream of the transcription start site

MAPPING

cloned

Y

linked

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	produces transcripts by different 5prime exons, which may be responsible for tissue-specific regulation (PMID: 21540083)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001450 6 - 1735 NP_001441 32 279 - 2011 21540083 NM_201557 6 - 1727 NP_963851 32 279 - 2011 21540083 NM_001039492 7 - 1552 NP_001034581 32 279 - 2011 21540083 NM_201555 8 - 1907 NP_963849 32 279 - 2011 21540083 NM_001374399 7 - 1503 NP_001361328 32 279 - 2011 21540083 NM_001318897 5 - 4375 NP_001305826 - 165 - 2011 21540083 NM_001318899 8 - 4690 NP_001305828 - 171 - 2011 21540083 NM_001318894 6 - 1798 NP_001305823 32 279 - 2011 21540083 NM_001318896 6 - 4517 NP_001305825 32 279 - 2011 21540083 NM_001318898 6 - 4521 NP_001305827 - 165 - 2011 21540083 NM_001318895 7 - 1582 NP_001305824 32 279 - 2011 21540083

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Homo sapiens Digestive intestine small intestine     lowly   intestine large intestine colon   lowly Reproductive female system ovary     highly   male system testis     lowly   male system prostate     lowly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone       Muscular cardiac myocardium     Homo sapiens Muscular smooth       Homo sapiens Muscular striatum cardiac

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	placenta, kidney

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four and a half LIM domains, each of which are composed of two zinc finger structures
	N-terminal half LIM domain followed by four complete LIM domains
	four and a half LIM domains, which share primary sequence pattern of cysteine and histidine with the RING domain, but are devoid of E3 ubiquitin ligase activity
	C terminal NXXY motif

HOMOLOGY

interspecies	homolog to murine Fhl2 (92.1pc)
	homolog to rattus Fhl2 (91.4pc)

Homologene

FAMILY

CATEGORY

adaptor , regulatory , signaling

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome
text	localize in Z-disc

basic FUNCTION	tissue specific coactivator of the androgen receptor, recruited to adhesion complexes FHL2/alpha and beta integrin chains
	negative regulator of E4F1
	having repressor function in cardiomyocytes through its ability to inhibit MAPK1/2 transcriptional coupling
	acting as a specific adaptor protein to couple metabolic enzymes to sites of high energy consumption in the cardiac sarcomere
	playing a role in heart muscle differentiation and in maintenance of the heart phenotype
	being an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated TNFRSF11A signaling
	can act on different aspects of the cell cycle program to finely regulate cell proliferation
	may function as a molecular transmitter linking various signaling pathways to transcriptional regulation
	role in bundling of focal adhesion structures, in integrin-mediated ERK activation, and subsequently in proper allocation of matrix proteins on the cell surface
	may regulate phosphatidylinositol 3-kinase/Akt via direct suppression of the SK1-S1P pathway in endothelial cells
	prevents the formation of ID2-E47 heterodimer by binding to ID2, thus releasing E47 to DNA and restoring its transcriptional activity
	association of FHL2 with NR4A1 plays a pivotal role in vascular disease
	represses the transcriptional activity of NR4A1 through interaction with the N-terminal and DBD of NR4A1 and enhances smooth muscle cell growth
	is a positive regulator of NFKB1 activity in liver regeneration and carcinogenesis
	importance of FHL2 in both hepatocytes and hepatic immune cells
	FHL1 and FHL2 are novel cardiac PRKD1 partners, which differentially facilitate PRKD1 activation and HDAC5 phosphorylation by distinct neurohormonal stimuli, but are unlikely to regulate MEF2A-driven transcriptional reprogramming
	FHL2 is regulated under the control of a tissue-specific promoter in hematopoietic cells and it is downregulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells
	FHL2 downregulation has likely a role in the pathogenesis of myeloid malignancies
	is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair
	is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts
	multifunctional adaptor protein that can interact with cell surface receptors, cytosolic adaptor and structural proteins, kinases, and nuclear transcription factors
	FHL2 seems to be involved in numerous steps of these extremely complex and multidirectional but tightly regulated tissue remodeling processes, supporting tissue repair and coordinating inflammation
	FHL2 is a scaffold protein involved in regulating vSMC function and inflammation
	anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply
	FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging
	is an anti-hypertrophic adaptor protein that regulates cardiac myocyte signalling and function

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

integrin signaling pathway

a component

component of focal adhesion structures

INTERACTION

DNA

RNA

small molecule

protein	coactivator of androgen receptor
	interacting with the DNA replication regulatory protein CDC47 (MCM7)
	interacting with MAPK2 through two LIM domains
	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)
	binding with NP220
	interacting with hydrophilic loop of PSEN2
	interacting and corepressing ZNF145
	bound to two distinct sites on titin
	interacting with CCND1 (critical for cyclin D1 activation and cell growth, regulate the activity of the cyclin D1 promoter through its implication in acetylation of transcription factors and histones)
	interacting with ZNF638, E4F1 and all members of the Id faily (Id1-4)
	potential KCNH2 partner (interacts with and regulates the KCNH2 channel)
	FHL1, FHL2, and FHL3 physically and functionally interact with SMAD2, SMAD3, and SMAD4, important regulators of cancer development and progression, in a TGF-beta-independent manner
	repressor of ID2
	FOXK1 interacting protein (FHL2, in a dose-dependent fashion, promotes FOXK1 transcriptional repression of FOXO4 activity)
	FHL2 is a novel regulator of CCL19-induced dendritic cell (DC) migration
	represses NR4A1 transcriptional activity in a dose-dependent manner
	directly interacts with HIF1A to repress transcriptional activity
	FHL2 controls the osteogenic differentiation of mesenchymal stromal cells (MSC), bone formation and bone mass through modulation of WNT molecules, WNT10B, WNT3A, WNT5A
	binds and synergistically cooperates with RNF111 to activate SMAD3/SMAD4-dependent transcription
	is important regulator of RNF111 ubiquitination and TGFB signal transduction
	FHL2 enhanced TRAF6 activity in transcriptional activation of NFKB1 targets by stabilizing the protein
	TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NFKB1 pathway
	is transcriptionally regulated by diverse types of transcription factors, for example, TP53, serum response factor (SRF), and specificity protein 1 (Sp1)
	exhibits specific interaction with proteins exhibiting diverse functions, including transmembrane receptors, transcription factors and transcription co-regulators, enzymes, and structural proteins
	is a critical regulator of TGFB1 expression
	FHL2, via modulating CTNNB1 signalling, may implicate in regulation of TGFB1-mediated tubular epithelial-to-mesenchymal transition (EMT)
	FHL2 decreases the inflammatory response of vascular smooth muscle cells (vSMCs) through inhibition of the NFKB1-signalling pathway
	CMYA5 is a novel FHL2 interaction partner in cardiac myocytes
	direct interaction of the two adaptor proteins FHL2 and CMYA5 in cardiac myocytes, which might impact subcellular compartmentation of CMYA5

cell & other

REGULATION

Other

up-regulated during retinoic acid-induced differenciation of neuroblastoma cells reducing the transcrptional and cell cycle promoting functions of ID2

ASSOCIATED DISORDERS

corresponding disease(s)

CMD1H

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in rhabdomyosarcoma constitutional       loss of function leads to impaired assembly of extracellular matrix proteins on the cell surface and to impaired bundling of focal adhesions tumoral       gain of function in colorectal cancer (CRC) compared with matched normal tissues

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive colon FOXK1 and FHL2 may serve as putative targets in the combined therapy of colorectal cancer

ANIMAL & CELL MODELS

up-regulation of Fhl2 may contribute to the antihypertrophic phenotype that is observed in cardiac-specific Rock2-deficient mice