Function: Vadlamudi et al. (2002) identified FLNA as a binding partner of PAK1 (OMIM:602590) in a yeast 2-hybrid screen of a mammary gland cDNA library. By mutation analysis, they localized the PAK1-binding region in FLNA to tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1 between amino acids 52 and 132 in the conserved CDC42 (OMIM:116952)/RAC (OMIM:602048)-interacting domain. Endogenous FLNA was phosphorylated by PAK1 on ser2152 following stimulation with physiologic signaling molecules. Following stimulation, FLNA colocalized with PAK1 in membrane ruffles. The ruffle-forming activity of PAK1 was found in FLNA-expressing cells, but not in cells deficient in FLNA.

Function: Androgen receptor (AR; OMIM:313700), a nuclear transcription factor, mediates male sexual differentiation. Loy et al. (2003) characterized a negative regulatory domain in the AR hinge region, which interacts with filamin A. Filamin A interferes with AR interdomain interactions and competes with the coactivator transcriptional intermediary factor-2 (TIF2; OMIM:601993) to downregulate AR function specifically. Although full-length filamin A is predominantly cytoplasmic, a C-terminal 100-kD fragment colocalized with AR to the nucleus. This naturally occurring filamin A fragment repressed AR transactivation and disrupted AR interdomain interactions and TIF2-activated AR function in a manner reminiscent of full-length filamin A, raising the possibility that the inhibitory effects of cytoplasmic filamin A may be transduced through this fragment, which can localize to the nucleus and form part of the preinitiation complex. This unanticipated role of filamin A added to the evidence for the involvement of cytoskeletal proteins in transcription regulation.

Function: Mutation in the X-linked FLNA gene can cause the neurologic disorder periventricular heterotopia (OMIM:300049). Although periventricular heterotopia is characterized by a failure in neuronal migration into the cerebral cortex with consequent formation of nodules in the ventricular and subventricular zones, many neurons appear to migrate normally, even in males, suggesting compensatory mechanisms. Sheen et al. (2002) showed that, in mice, Flna mRNA was widely expressed in all brain cortical layers, whereas a homolog, Flnb (OMIM:603381), was most highly expressed in the ventricular and subventricular zones during development. In adulthood, widespread but reduced expression of Flna and Flnb persisted throughout the cerebral cortex. Flna and Flnb proteins were highly expressed in both the leading processes and somata of migratory neurons during corticogenesis. Postnatally, Flna immunoreactivity was largely localized to the cell body, whereas Flnb was localized to the soma and neuropil during neuronal differentiation. The putative Flnb homodimerization domain strongly interacted with itself or the corresponding homologous region of Flna, as shown by yeast 2-hybrid interaction. The 2 proteins colocalized within neuronal precursors by immunocytochemistry, and the existence of Flna-Flnb heterodimers could be detected by coimmunoprecipitation. Sheen et al. (2002) suggested that FLNA and FLNB may form both homodimers and heterodimers, and that their interaction could potentially compensate for the loss of FLNA function during cortical development within patients with periventricular heterotopia.

Function: Using a yeast 2-hybrid screen, Grimbert et al. (2004) identified FLNA as a binding partner for both CMIP (OMIM:610112) and its truncated isoform, TCMIP. Coimmunoprecipitation analysis confirmed the interactions. Immunofluorescence microscopy demonstrated homogeneous colocalization of CMIP and FLNA in the cytoplasm, but restriction of TCMIP/FLNA colocalization to points of intercellular contact. Western blot analysis showed increased FLNA expression in patients with relapse of minimal change nephrotic syndrome, a glomerular disease thought to result from abnormal T-cell activation. Grimbert et al. (2004) proposed that FLNA and CMIP/TCMIP interact in a T-cell signaling pathway.

Function: Using proteomic approaches, Thelin et al. (2007) showed that FLNA associates with the extreme CFTR (OMIM:602421) N terminus. Cell studies revealed that filamin tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded.

Function: Using yeast 2-hybrid analysis and protein pull-down assays, Jimenez-Baranda et al. (2007) showed that the human immunodeficiency virus (HIV)-1 (see OMIM:609423) receptor CD4 (OMIM:186940) and the HIV-1 coreceptors CCR5 (OMIM:601373) and CXCR4 (OMIM:162643) interacted with FLNA, which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; OMIM:601442) phosphorylation inactivation through a RHOA (OMIM:165390)-ROCK (see OMIM:601702)-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. Jimenez-Baranda et al. (2007) concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection.

Summary

Top-ranked sequences

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            ||||||||||||||||||||||||||||||#||||||||||||||||||||||||||||||
Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            ||||||||||||||||||||||||||||||#|||||||||||||||+||||||||||||||
Sbjct  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDMTSLRPFDLVIPFTI 1799

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |||||||+ ||||| ||||| |||||||||#||||||||+|||||||||||||||||||||
Sbjct  1740 ALAGDQPAAQPPLRPQQLAPPYTYAQGGQQ#TWAPERPLMGVNGLDVTSLRPFDLVIPFTI 1799

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |||||||+ || || ||||| |||||||||#||||||||||||||||+|||||||||||||
Sbjct  2023 ALAGDQPTAQPSLRPQQLAPPYTYAQGGQQ#TWAPERPLVGVNGLDVSSLRPFDLVIPFTI 2082

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |||||||+|| ||||||||||| | || ||#|| ||||+||||||||||||||||||||||
Sbjct  1732 ALAGDQPTVQTPLRSQQLAPQYNYPQGSQQ#TWIPERPMVGVNGLDVTSLRPFDLVIPFTI 1791

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |||||||+|| ||||||||||| | || ||#|| ||||+||||||||||||||||||||||
Sbjct  1740 ALAGDQPTVQTPLRSQQLAPQYNYPQGSQQ#TWIPERPMVGVNGLDVTSLRPFDLVIPFTI 1799

Query  1740 ALAGDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |||||||+|| ||| |||  |||| || ||#|| ||||+||||||||||||||||||||||
Sbjct  1740 ALAGDQPTVQTPLRPQQLPSQYTYPQGSQQ#TWIPERPMVGVNGLDVTSLRPFDLVIPFTI 1799

Query  1769 Q#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |#  | ||||+|||||||  ||||||||| ||
Sbjct  1719 Q#VMATERPLLGVNGLDV-GLRPFDLVIPLTI 1748

Query  1772 APERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            | +||+ |+|||||  ||||||||||||
Sbjct  1718 ATDRPM-GMNGLDVAGLRPFDLVIPFTI 1744

Query  1743 GDQPSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            |  | + | +     + ++|+ +  | #||  |   | |+ ++    +|||||||| +
Sbjct  1719 GQYPGLSPGILKDNSSEKHTFMKTKQL#TWVTEEAYVPVSNMNGLGFKPFDLVIPFAV 1775

Query  1746 PSVQPPLRSQQLAPQYTYAQGGQQ#TWAPERPLVGVNGLDVTSLRPFDLVIPFTI 1799
            | ++ |    ||   |   ||   # || | |+  |+ ++   ||||+||||||+
Sbjct  1276 PIIEEPCDKLQLQQPYAPYQGYSP#HWATEEPVTAVDIIEPV-LRPFNLVIPFTV 1328

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[PubMed ID: 1833070] ... Ohta Y, Stossel TP, Hartwig JH, Ligand-sensitive binding of actin-binding protein to immunoglobulin G Fc receptor I (Fc gamma RI). Cell. 1991 Oct 18;67(2):275-82.

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