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FLASH GENE

Symbol

FLNA

contributors: mct - updated : 27-02-2017

HGNC name	filamin A, alpha
HGNC id	3754

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BPNH bilateral periventricular nodular heterotopia in females CIPO2 intestinal pseudoobstruction, neuronal, chronic idiopathic 2 FGS2 FG syndrome 2 FMTD frontometaphyseal dysplasia MLNS Melnick-Needles syndrome ODPF terminous osseous dysplasia and pigmentary defect OPD1 otopalatodigital syndrome, type 1 OPD2 otopalatodigital syndrome, type 2 PVNH4 periventricular heterotopia 4, Ehlers-Danlos variant
Location	Xq28      Physical location : 153.576.899 - 153.603.006
Synonym name	filamin A, alpha (actin binding protein 280)
	actin binding phosphoprotein, dystrophin-like (APB280)
	actin binding protein 280
	endothelial actin-binding protein
	non-muscle filamin
Synonym symbol(s)	ABP280, ABPX, FLN1, NHBP, MNS, FMD, DKFZp434P031

DNA

TYPE	functioning gene
STRUCTURE	26.11 kb     48 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - RGCP@ - TKTL1 - FLNA - EMD EMD - DNASE1L1 - TAZ - ATP6AP1 - GDI1 - (FAM50A - PLXNA3 ) - LAGE3 - UBL4A - (SLC10A3 )- DXS253E - FAM3A - G6PD - ERVK2 - MPP1 - F8 - DXS115 - DXS459 - DXYS64X - qter
Authors	PMID: 8577758
Text	see CVG@

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001110556 48 - 8557 NP_001104026 280 2647 - 2001 11336782 NM_001456 47 - 8533 NP_001447 - 2639 - 2001 11336782

EXPRESSION

Type	ubiquitous

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 Digestive esophagus       highly Reproductive female system uterus     highly   male system prostate     highly Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone       Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	highly, in the cortex (migratory neurons)

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal filamentous with two calponin
	homology domains (CHD1 and CHD2, actin-binding domain (ABD), between the initial two methionines crucial for proper enteric neuron development, and calponin homology domain 1 (CHD1), within the filamin A (FLNa) actin-binding domain, is the minimal fragment sufficient for ASB2-mediated degradation
	24 Ig-like domains, filamin repeats terminating in a 24th-dimerisation domain
	a membrane glycoprotein binding domain
	C terminal self-association domain

mono polymer

homomer , heteromer , dimer

HOMOLOGY

interspecies

homolog to murine Flna

intraspecies

homolog to flnc

Homologene

FAMILY

filamin family

CATEGORY

chaperone/stress , motor/contractile , signaling

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus,nucleolus
text	localize to podosomes, and the defects seen in patients carrying FLNA mutations could be related to the capacity of certain cell types to form podosomes

basic FUNCTION	dimeric actin cross-linking phosphoprotein
	required for locomotion of many cell types
	anchor protein, playing essential roles in intercellular junctions
	having a critical function in neural-crest and non-neural crest, and playing a role either in organizing endothelial cells or in the interaction of endothelial and mesenchymal cells
	required for cell-cell contact in vascular development and cardiac morphogenesis
	playing a crucial role in enteric-neuron structure and function
	playing an important role in actin cytoskeleton organization, membrane stabilization, and anchoring of transmembrane proteins
	involved in Ca2+ -sensing receptor signaling (silencing of filamin A gene expression inhibits Ca2+ -sensing receptor signaling)
	CAV1-dependent target in IGF1-stimulated cancer cell migration
	required for an efficient recombinational DNA double strand break repair
	required for membrane stability, providing protection from force-induced cell death in an integrin-dependent manner for which the AB Domain is essential
	enhances MAP2K7 activation and is important for synergistic stress-induced JNK activation
	actin-binding protein that participates in cell attachment, plays important additional roles in signal transduction and modulation of transcriptional responses
	stimulates CDC25C function and promotes entry into mitosis
	required to maintain the F-actin-dependent linear distribution of caveolin-1
	plays a critical role in cytoskeletal organization, cell motility and cellular signaling
	actin-binding protein that is a central mechanotransduction element of the cytoskeleton
	has a crucial role in the normal processes of ciliogenesis and basal body positioning
	role in mesenchymal migration, which could be directly related to the defects in cell migration described during the embryonic development in FLNA-defective patients
	unique role for FLNA as a nucleolar protein that associates with the RNA polymerase I (Pol I) transcription machinery to suppress rRNA gene transcription
	positive role for FLNA in platelet adhesion under high shear
	non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers
	ASB2-resistant filamins protect cells from ASB2-mediated inhibition of spreading

CELLULAR PROCESS

cell communication

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	heterodimer FLNA/FLNB
	repeat 24 and the second hinge domain are important for dimer formation
	dimeric protein that binds to actin filaments via its actin-binding domain
	forms
	V
	-shaped tail-to-tail homodimers that cross-link F-actin into orthogonal networks
	forms a complex with CDC25C and binds preferentially to the mitotic form of CDC25C

INTERACTION

DNA

RNA

small molecule

protein	LNK regulatory role through its association with LNK
	FLNB to allow for proper neuronal migration
	SP1 transcriptional activation
	interacting with MAP3K4
	ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation
	interactions between FLNA and transmembrane or signalling proteins, mediated at least in part by immunoglobulin domains 19 to 21 are important for both cell spreading and initiation of migration can bind MAP2K7 and MAP2K4, connecting the in close proximity
	interacting with IGFBP5 (IGFBP5 leads to dephosphorylation of FLNA with subsequent FLNA cleavage)
	interacting with CFTR
	in melanoma cells RRAS and FLNA may cooperatively promote metastasis by enhancing cell migration
	interactions with intermediate filaments and protein kinase C enable tight regulation of ITGB1 function and consequently early events in cell adhesion and migration on extracellular matrix proteins
	in endothelial cells endogenous RRAS interacts with endogenous FLNA, to maintain endothelial barrier function
	TMEM67 forms a functional complex with FLNA that is disrupted in MKS3 and causes defects in neuronal migration and Wnt signalling
	NPHS1 recruits and regulates a protein complex that includes INPPL1, FLNA and RAPH1, proteins important in regulation of actin and focal adhesion dynamics, as well as lamellipodia formation
	FLNA, FLNB but not Janus kinases are substrates of the ASB2 cullin-ring E3 ubiquitin ligase in hematopoietic cells
	ARFGEF2 regulates filamin A phosphorylation and neuronal migration
	reduces SCNN1A channel function through direct interaction on the cell surface
	FLNA binds to ARHGAP24 at F-actin-enriched sites, such as at the leading edge of the cell where RAC1 activity is controlled to inhibit actin assembly
	FLNA regulates neuronal migration through ARFGEF2-dependent ARF1 activation
	interaction between the antiviral endoribonuclease RNASEL and the actin-binding protein FLNA that enhances host defense by preventing viral entry into naive cells
	RCAN1 acts upstream from FLNA in regulating radial migration, suggesting that impairment of RCAN1-FLNA pathway may underlie Periventricular heterotopia (PH) pathogenesis
	FLNA-PACSIN2 interaction regulates membrane tubulation in megakaryocyte (MK) and platelets and likely contributes to demarcation membrane system (DMS)formation
	ASB2, by driving degradation of filamin A (FLNA) and filamin B (FLNB), is responsible for the difference in FLNA and FLNB abundance in the different spleen Conventional dendritic cells (cDCs) subsets
	FLNA loss leads to diminished expression of Beta1-integrin, whereas FLNB loss promotes integrin expression
	FLNA is known to play roles in cytoskeleton organization and to be required for heart function, and its degradation mediated by ASB2 ensures essential functions in differentiating cardiac progenitors
	LXN interacts with Filamin A (FLNA) and regulates FLNA proteolytic cleavage and nuclei translocation

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

BPNH , OPD2 , MLNS , FMTD , OPD1 , PVNH4 , CIPO2 , FGS2 , ODPF

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   inhibited neuronal migration

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS