the first two exons are thought to be noncoding, exons 3 to 8 are alternatively spliced and give rise to three major transcribed isoforms: FHL1A, FHL1B, and FHL1C (PMID: 19716112)
identification
nb exons
type
bp
product
Protein
kDa
AA
specific expression
Year
Pubmed
7
splicing
2455
31.5
280
. predominantly expressed in skeletal and cardiac striated muscles
. expressed in many cell types, with highest levels in skeletal muscle, intermediate levels in the heart and low expression in placenta, ovary, prostate, testis, small intestine, colon and spleen
2012
22523091
also called FHL1A/SLIM1
localizing at focal adhesions
4.5 LIM domains
8
splicing
2724
-
323
. nuclear
. in striated muscles and also in brain
. expressed in brain, skeletal muscle and, to a lesser extent, in heart, colon, prostate and small intestine
2012
22523093
FHL1B/SLIM3, slimmer
lack exon 4 and contain a C-terminal putative binding domain for J-recombination signal protein (RBP-J)
interacts with SIVA1 and delays skeletal myoblast apoptosis (PMID: 19643733)
shuttle between nucleus and cytoplasm at different phases of the cell cycle
FHL1B/PPP2CA interaction may illustrate a novel cell-cycle regulatory pathway (PMID: 20969868)
one of the roles of FHL1B is to act as a specific regulator of PPP2CA in human muscles and brain (PMID: 20969868)
contains the LIM domains 1–3 plus nuclear localization and export signals, as well as an RBP-J binding region
6
-
2906
-
280
-
-
6
-
2331
-
309
-
1999
9929984
6
-
2337
-
194
-
1999
9929984
7
-
2524
-
280
-
1999
9929984
7
splicing
2392
-
280
. specifically expressed in testis, skeletal muscle, and heart at a relatively low level, also seen in aorta, left atrium, left, and right ventricles at low level
. expressed at much lower levels in heart, testis and skeletal muscle
2011
22053194
also called isoform FHL1C, or KyoT2
loss of exon 4
contains a single zinc finger and two tandem repeats of LIM domains at the N-terminus followed by a putative RBP-J binding region at the C-terminus
homolog of murine Kyot2
localized both in the nucleus and cytoplasm
2.5 LIM domains
is a binding partner for KCNA5
FHL1C could induce TJP1 translocating into nucleus, and could contribute to the epithelial-mesenchymal transition (EMT) (PMID: 24657059)
6
-
2460
-
296
-
1999
9929984
EXPRESSION
Type
widely
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
predominantly
Homo sapiens
Adult
Digestive
liver
moderately
mouth
tongue
highly
Nervous
brain
moderately
Reproductive
female system
placenta
moderately
Respiratory
lung
moderately
Urinary
kidney
moderately
tissue
System
Tissue
Tissue level 1
Tissue level 2
Level
Pubmed
Species
Stage
Rna symbol
Muscular
striatum
skeletal
highly
Homo sapiens
Muscular
striatum
cardiac
highly
Homo sapiens
Adult
cells
System
Cell
Pubmed
Species
Stage
Rna symbol
Muscular
myocyte
Homo sapiens
cell lineage
myoblasts, myotubes
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
four and a half LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences constituted by two zinc fingers in tandem, implicated in numerous interactions
a novel C terminal 96 AAs with three potential nuclear localization signals (NLS)
a putative nuclear export sequence and 27AA identical to the RBPJ region of KyoT2
with isoforms FHL1A, FHL1B,(SLIM1) localizing at focal adhesions and SLIM3 (slimmer) in the nucleus of myoblasts and cytoplasm of myotubes
can be localized to the sarcolemma, sarcomere, and nucleus of muscle cells
localized within the cytoskeleton and the nucleus and can shuttle between these compartments
mainly localize to the sarcomeric I-band, but also to a lesser extent to the M-band of the sarcomere in skeletal myocytes
basic FUNCTION
sugesting distinct roles in the cytoskeleton and in nuclear-cytoplasmic communication
probably related to neural differentiation
playing a role in the development and maintenance of muscle tissue, in sarcomere synthesis and assembly
regulator of myosin-binding protein C activity and playinga role in sarcomere assembly
LIM domain protein that suppresses the RBPJ-mediated transcriptional activation
might inhibit the RBPJ-mediated transactivation through intracellular domain of Notch by recruiting co-suppressors such as CBX4
implicated in sarcomere assembly by interacting with myosin binding protein-C
suggested to contribute to sarcomere synthesis, assembly and biomechanical stress sensing
cooperative regulation of VEGFA signaling by FHL1 and SMAD4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression
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
can be an acting molecule mediating both signaling pathways during osteogenesis
CELLULAR PROCESS
PHYSIOLOGICAL PROCESS
PATHWAY
metabolism
signaling
a component
FHL1 exists as part of a complex that binds with PDLIM1, GSN and ACTN1
INTERACTION
DNA
RNA
small molecule
protein
interacting with AKAP1 and FRAP1 for regulating ribosomal protein genes
interacting with myosin-binding protein C (MYBPC), and may contribute to muscle cytoarchitecture by interacting
interacting with CBX4
talin1 is a new interacting partner of FHL1
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
interaction between ubiquitin-specific protease 15 (USP15) and skeletal muscle LIM protein 1 (FHL1)
binds to the EP300/CREBBP co-activators and disrupts binding with HIF1A
FHL1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics
NFATC1-mediated transcription regulates UTRN expression and FHL1 which promotes muscle hypertrophy, is a transcriptional activator of NFATC1
binds RBPJ with high affinity and competes with coactivators, such as NOTCH1, for binding RBPJ
cell & other
REGULATION
Other
regulated by TLX1
regulation is hypoxia-inducible transcription factor dependent
particularly in the pulmonary vasculature, in lungs from patients with idiopathic pulmonary arterial hypertension
constitutional
--low
in hypertrophic cardiomyopathy and failing hearts
constitutional
--over
in hypertrophic cardiomyopathy (HCM)
constitutional
--over
in smooth muscle in Hirschsprung disease (HSCR) might be associated with intestinal wall remodeling in HSCR and might be one of the risk factors for gastrointestinal motor dysfunction
Susceptibility
Variant & Polymorphism
Candidate gene
Marker
Therapy target
System
Type
Disorder
Pubmed
neuromuscular
myopathy
FHL1-NFATC1-UTRN signaling axis that can functionally compensate for dystrophin and treat DMD
ANIMAL & CELL MODELS
W122S mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle, and loss of function is responsible for the late-onset mild myopathy in the Fhl1 W122S knock-in mice
