FLNA

The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

Filamin A

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).

Actin crosslink formation Source: BHF-UCL
Actin cytoskeleton reorganization Source: BHF-UCL
Adenylate cyclase-inhibiting dopamine receptor signaling pathway Source: BHF-UCL
Angiogenesis Source: Ensembl
Blood vessel remodeling Source: Ensembl
Cell-cell junction organization Source: Ensembl
Cerebral cortex development Source: Ensembl
Cilium assembly Source: UniProtKB
Cytoplasmic sequestering of protein Source: BHF-UCL
Early endosome to late endosome transport Source: Ensembl
Epithelial to mesenchymal transition Source: Ensembl
Establishment of protein localization Source: BHF-UCL
Establishment of Sertoli cell barrier Source: Ensembl
Formation of radial glial scaffolds Source: Ensembl
Heart morphogenesis Source: Ensembl
Mitotic spindle assembly Source: MGI
mRNA transcription by RNA polymerase II Source: Ensembl
Negative regulation of apoptotic process Source: CACAO
Negative regulation of DNA-binding transcription factor activity Source: UniProtKB
Negative regulation of neuron projection development Source: Ensembl
Negative regulation of protein catabolic process Source: BHF-UCL
Negative regulation of transcription by RNA polymerase I Source: CACAO
Platelet aggregation Source: UniProtKB
Positive regulation of actin filament bundle assembly Source: Ensembl
Positive regulation of axon regeneration Source: Ensembl
Positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Positive regulation of integrin-mediated signaling pathway Source: CACAO
Positive regulation of neural precursor cell proliferation Source: Ensembl
Positive regulation of neuron migration Source: Ensembl
Positive regulation of potassium ion transmembrane transport Source: BHF-UCL
Positive regulation of protein import into nucleus Source: UniProtKB
Positive regulation of substrate adhesion-dependent cell spreading Source: CACAO
Protein localization to bicellular tight junction Source: Ensembl
Protein localization to cell surface Source: BHF-UCL
Protein localization to plasma membrane Source: BHF-UCL
Protein stabilization Source: BHF-UCL
Receptor clustering Source: BHF-UCL
Regulation of cell migration Source: UniProtKB
Regulation of membrane repolarization during atrial cardiac muscle cell action potential Source: BHF-UCL
Regulation of membrane repolarization during cardiac muscle cell action potential Source: BHF-UCL
Semaphorin-plexin signaling pathway Source: WormBase
Synapse organization Source: Ensembl
Tubulin deacetylation Source: CACAO
Wound healing, spreading of cells Source: UniProtKB

Cytoskeleton; Cell cortex; Perikaryon; Growth cone. 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).

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.
Otopalatodigital syndrome 1 (OPD1):
X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, 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.
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.
Frontometaphyseal dysplasia 1 (FMD1):
An X-linked disease characterized by generalized skeletal dysplasia, deafness, and urogenital defects.
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.
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.
FG syndrome 2 (FGS2):
FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.
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.
Cardiac valvular dysplasia, X-linked (CVD1):
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.
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.

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).