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PMID:12807912

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Citation

Vartiainen, MK, Sarkkinen, EM, Matilainen, T, Salminen, M and Lappalainen, P (2003) Mammals have two twinfilin isoforms whose subcellular localizations and tissue distributions are differentially regulated. J. Biol. Chem. 278:34347-55

Abstract

Twinfilin is a highly conserved actin monomer-binding protein that regulates cytoskeletal dynamics in organisms from yeast to mammals. In addition to the previously characterized mammalian twinfilin-1, a second protein with approximately 65% sequence identity to twinfilin-1 exists in mouse and humans. However, previous studies failed to identify any actin binding activity in this protein (Rohwer, A., Kittstein, W., Marks, F., and Gschwendt, M. (1999) Eur. J. Biochem. 263, 518-525). Here we show that this protein, which we named twinfilin-2, is indeed an actin monomer-binding protein. Similar to twinfilin-1, mouse twinfilin-2 binds ADP-G-actin with a higher affinity (KD = 0.12 microM) than ATP-G-actin (KD = 1.96 microM) and efficiently inhibits actin filament assembly in vitro. Both mouse twinfilins inhibit the nucleotide exchange on actin monomers and directly interact with capping protein. Furthermore, the actin interactions of mouse twinfilin-1 and twinfilin-2 are inhibited by phosphatidylinositol (4,5)-bisphosphate. Although biochemically very similar, our Northern blots and in situ hybridizations show that these two proteins display distinct expression patterns. Twinfilin-1 is the major isoform in embryos and in most adult mouse non-muscle cell-types, whereas twinfilin-2 is the predominant isoform of adult heart and skeletal muscles. Studies with isoform-specific antibodies demonstrated that although the two proteins show similar localizations in unstimulated cells, they are regulated by different mechanisms. The small GTPases Rac1 and Cdc42 induce the redistribution of twinfilin-1 to membrane ruffles and cell-cell contacts, respectively, but do not affect the localization of twinfilin-2. Taken together, these data show that mammals have two twinfilin isoforms, which are differentially expressed and regulated through distinct cellular signaling pathways.

Links

PubMed Online version:10.1074/jbc.M303642200

Keywords

3T3 Cells; Actins/chemistry; Actins/metabolism; Amino Acid Sequence; Animals; Blotting, Northern; Blotting, Western; Carrier Proteins; Cell Communication; Cells, Cultured; Cytoskeleton/metabolism; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Glutathione Transferase/metabolism; Humans; In Situ Hybridization; Kinetics; Mice; Microfilament Proteins/chemistry; Microscopy, Fluorescence; Molecular Sequence Data; Phosphatidylinositol 4,5-Diphosphate/chemistry; Plasmids/metabolism; Protein Binding; Protein Isoforms; Protein Structure, Tertiary; Protein-Tyrosine Kinases; RNA/metabolism; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins; Signal Transduction; Time Factors; Tissue Distribution; Tumor Cells, Cultured; cdc42 GTP-Binding Protein/chemistry; rac1 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TWF1

enables

GO:0005546: phosphatidylinositol-4,5-bisphosphate binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

F

Seeded From UniProt

complete

HUMAN:TWF1

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

C

Seeded From UniProt

complete

HUMAN:TWF1

located_in

GO:0030175: filopodium

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

C

Seeded From UniProt

complete

HUMAN:TWF1

involved_in

GO:0030837: negative regulation of actin filament polymerization

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

P

Seeded From UniProt

complete

HUMAN:TWF1

enables

GO:0003785: actin monomer binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

F

Seeded From UniProt

complete

HUMAN:TWF1

colocalizes_with

GO:0032587: ruffle membrane

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

C

Seeded From UniProt

complete

HUMAN:TWF1

located_in

GO:0005911: cell-cell junction

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q91YR1

C

Seeded From UniProt

complete

HUMAN:TWF2

enables

GO:0005546: phosphatidylinositol-4,5-bisphosphate binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

F

Seeded From UniProt

complete

HUMAN:TWF2

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

C

Seeded From UniProt

complete

HUMAN:TWF2

located_in

GO:0030175: filopodium

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

C

Seeded From UniProt

complete

HUMAN:TWF2

involved_in

GO:0030837: negative regulation of actin filament polymerization

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

P

Seeded From UniProt

complete

HUMAN:TWF2

located_in

GO:0030027: lamellipodium

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

C

Seeded From UniProt

complete

HUMAN:TWF2

enables

GO:0003785: actin monomer binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9Z0P5

F

Seeded From UniProt

complete

MOUSE:TWF1

enables

GO:0005546: phosphatidylinositol-4,5-bisphosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TWF1

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF1

located_in

GO:0030175: filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF1

involved_in

GO:0030837: negative regulation of actin filament polymerization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TWF1

enables

GO:0003785: actin monomer binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TWF1

colocalizes_with

GO:0032587: ruffle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF1

located_in

GO:0005911: cell-cell junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF2

enables

GO:0005546: phosphatidylinositol-4,5-bisphosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TWF2

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF2

located_in

GO:0030175: filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWF2

involved_in

GO:0030837: negative regulation of actin filament polymerization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TWF2

enables

GO:0003785: actin monomer binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TWF2

located_in

GO:0030027: lamellipodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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