FLNA
Domain
Comprised of a NH2-terminal actin-binding domain, 24 immunoglobulin-like internally homologous repeats and two hinge regions. Repeat 24 and the second hinge domain are important for dimer formation. Filamin repeat 20 interacts with filamin repeat 21 masking the ligand binding site on filamin repeat 21, resulting in an autoinhibited conformation (PubMed:17690686). The autoinhibition can be relieved by ligands like ITGB7 or FBLIM1 (PubMed:21524097). Filamin repeats 19 and 21 can simultaneously engage ligands (PubMed:21524097).
Function
Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance (By similarity). During the axon guidance process, required for growth cone collapse induced by SEMA3A-mediated stimulation of neurons (PubMed:25358863).
Involvement in disease
Periventricular nodular heterotopia 1
PVNH1
A developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period.
None
The disease is caused by variants affecting the gene represented in this entry.
Otopalatodigital syndrome 1
OPD1
X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild intellectual disability, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum.
None
The disease is caused by variants affecting the gene represented in this entry.
Otopalatodigital syndrome 2
OPD2
Congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects.
None
The disease is caused by variants affecting the gene represented in this entry.
Frontometaphyseal dysplasia 1
FMD1
An X-linked disease characterized by generalized skeletal dysplasia, deafness, and urogenital defects.
None
The disease is caused by variants affecting the gene represented in this entry.
Melnick-Needles syndrome
MNS
Severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull.
None
The disease is caused by variants affecting the gene represented in this entry.
Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
IPOX
A disease characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion.
None
The disease is caused by variants affecting the gene represented in this entry.
FG syndrome 2
FGS2
FG syndrome (FGS) is an X-linked disorder characterized by intellectual disability, relative macrocephaly, hypotonia and constipation.
None
The disease is caused by variants affecting the gene represented in this entry.
Terminal osseous dysplasia
TOD
A rare X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females.
None
The disease is caused by variants affecting the gene represented in this entry.
Cardiac valvular dysplasia, X-linked
CVDPX
A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets.
None
The disease is caused by variants affecting the gene represented in this entry.
Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abnormally enlarged (PubMed:21960593).
Congenital short bowel syndrome, X-linked
CSBSX
A disease characterized by a shortened small intestine, and malabsorption. The mean length of the small intestine in affected individuals is approximately 50 cm, compared with a normal length at birth of 190-280 cm. It is associated with significant mortality and morbidity. Infants usually present with failure to thrive, recurrent vomiting, and diarrhea.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation at Ser-2152 is negatively regulated by the autoinhibited conformation of filamin repeats 19-21. Ligand binding induces a conformational switch triggering phosphorylation at Ser-2152 by PKA.
Phosphorylation extent changes in response to cell activation.
Polyubiquitination in the CH1 domain by a SCF-like complex containing ASB2 leads to proteasomal degradation. Prior dissociation from actin may be required to expose the target lysines (PubMed:24052262). Ubiquitinated in endothelial cells by RNF213 downstream of the non-canonical Wnt signaling pathway, leading to its degradation by the proteasome (PubMed:26766444).
Sequence Similarities
Belongs to the filamin family.
Tissue Specificity
Ubiquitous.
Cellular localization
- Cytoplasm
- Cell cortex
- Cytoplasm
- Cytoskeleton
- Perikaryon
- Cell projection
- Growth cone
- Cell projection
- Podosome
- Colocalizes with CPMR1 in the central region of DRG neuron growth cone (By similarity). Following SEMA3A stimulation of DRG neurons, colocalizes with F-actin (By similarity). Localized to the core of myotube podosomes (By similarity).
Alternative names
FLN, FLN1, FLNA, Filamin-A, FLN-A, Actin-binding protein 280, Alpha-filamin, Endothelial actin-binding protein, Filamin-1, Non-muscle filamin, ABP-280