Alternative titles; symbols
HGNC Approved Gene Symbol: FBLIM1
Cytogenetic location: 1p36.21 Genomic coordinates (GRCh38) : 1:15,756,638-15,786,589 (from NCBI)
By yeast 2-hybrid analysis using MIG2 (607746) as bait, Tu et al. (2003) cloned migfilin from a lung cDNA library. The predicted 373-amino acid migfilin protein contains an N-terminal region, a central proline-rich region, and 3 C-terminal LIM domains. PCR analysis identified a variant cDNA that encodes a protein identical to migfilin except that it lacks the proline-rich region. The human and mouse migfilin proteins share 78% amino acid identity. Western blot analysis indicated that migfilin is widely expressed in human cells. Immunofluorescence analysis showed that both migfilin variants colocalize with MIG2 at cell-extracellular matrix (ECM) adhesions where actin stress fibers are anchored.
Using repeats 10 to 18 of filamin B (FLNB; 603381) as bait in a yeast 2-hybrid screen, followed by 5-prime RACE, Takafuta et al. (2003) cloned FBLP1 from a placenta cDNA library. The deduced 374-amino acid protein has a leucine-rich nuclear export signal, an N-terminal proline-rich domain, and 2 LIM domains. Takafuta et al. (2003) also identified 2 FBLP1 splice variants that encode proteins of 373 and 276 amino acids, both of which contain 3 LIM domains, although the shorter variant lacks the proline-rich domain. RT-PCR showed expression of FBLP1 in all tissues examined, with some tissue-specific expression of the isoforms.
Cell-ECM adhesion is an important determinant of cell morphology. Tu et al. (2003) showed that migfilin localizes to cell-ECM adhesions, associates with actin filaments, and is essential for cell shape modulation. They determined that migfilin interacts with MIG2 and the actin-binding protein filamin (see 300017) through its C- and N-terminal domains, respectively. Loss of MIG2 or migfilin impaired cell shape modulation. The authors demonstrated that MIG2 recruits migfilin to cell-ECM adhesions, while the interaction with filamin mediates the association of migfilin with actin filaments. Tu et al. (2003) concluded that migfilin functions as an important scaffold at cell-ECM adhesions. They proposed that, together, MIG2, migfilin, and filamin define a connection between ECM adhesions and the actin cytoskeleton and participate in the orchestration of actin assembly and cell shape modulation.
By yeast 2-hybrid assay using truncation mutants of FLNB, Takafuta et al. (2003) determined that FBLP1 interacts with FLNB between repeats 10 and 13. Overexpression of FBLP1 in embryonic kidney cells increased stress fiber formation. While FLNB distributed diffusely throughout the cytoplasm of nontransfected cells, both FLNB and FBLP1 localized to stress fibers following FBLP1 transfection and overexpression. FLNA (300017) also colocalized with FBLP1 at stress fibers.
Takafuta et al. (2003) determined that the FBLP1 gene contains 8 exons.
By genomic sequence analysis, Takafuta et al. (2003) mapped the FBLP1 gene to chromosome 1p36.13.
Associations Pending Confirmation
For discussion of a possible association between variation in the FBLIM1 gene and chronic recurrent multifocal osteomyelitis, see CRMO (259680).
Using a conditional floxed allele of the Fblim1 gene, Moik et al. (2011) generated a migfilin-null mouse strain. The mutant mice were viable and showed normal development. Examination of migfilin-null heart, lung, kidney, and colon revealed no abnormalities, and apoptosis was normal in all organs tested. Fibroblasts and keratinocytes from migfilin-null mice displayed normal spreading and adhesion, and normal integrin (see 192968) expression and activation. The migration velocity and directionality of migfilin-null embryonic fibroblasts were normal, whereas the velocity of migfilin-null keratinocytes in wound scratch assays was slightly but significantly reduced. The authors concluded that the roles of migfilin are functionally redundant during mouse development and tissue homeostasis.
Xiao et al. (2012) generated Fblim1 -/- mice and observed a severe osteopenic phenotype, with a significant reduction in bone/tissue volume and trabecular number and a marked increase in trabecular space compared to wildtype littermates. Primary Fblp1-null bone marrow stromal cells (BMSCs) exhibited significantly reduced extracellular matrix adhesion and migration compared with wildtype BMSCs. Loss of Fblp1 significantly impaired growth and survival of BMSCs in vitro and decreased the number of osteoblast progenitors in bone marrow and osteoblast differentiation in vivo. A dramatic increase in osteoclast differentiation was also observed in vivo, and the level of RANKL (TNSF11; 602642), a key regulator of OCL differentiation, was markedly increased in Fblp1-null BMSCs. In addition, loss of Fblp1 promoted activating phosphorylation of ERK1 (MAPK3; 601795)/2 (MAPK1; 176948), and inhibition of ERK1/2 activation substantially suppressed the RANKL increase induced by loss of Fblp1. The authors concluded that FBLP1 is a key regulator of bone homeostasis.
Moik, D. V., Janbandhu, V. C., Fassler, R. Loss of migfilin expression has no overt consequences on murine development and homeostasis. J. Cell Sci. 124: 414-421, 2011. [PubMed: 21224394] [Full Text: https://doi.org/10.1242/jcs.075960]
Takafuta, T., Saeki, M., Fujimoto, T.-T., Fujimura, K., Shapiro, S. S. A new member of the LIM protein family binds to filamin B and localizes at stress fibers. J. Biol. Chem. 278: 12175-12181, 2003. [PubMed: 12496242] [Full Text: https://doi.org/10.1074/jbc.M209339200]
Tu, Y., Wu, S., Shi, X., Chen, K., Wu, C. Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell 113: 37-47, 2003. [PubMed: 12679033] [Full Text: https://doi.org/10.1016/s0092-8674(03)00163-6]
Xiao, G., Cheng, H., Cao, H., Chen, K., Tu, Y., Yu, S., Jiao, H., Yang, S., Im, H.-J., Chen, D., Chen, J., Wu, C. Critical role of filamin-binding LIM protein 1 (FBLP-1)/migfilin in regulation of bone remodeling. J. Biol. Chem. 287: 21450-21460, 2012. [PubMed: 22556421] [Full Text: https://doi.org/10.1074/jbc.M111.331249]