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J. Biol. Chem., Vol. 278, Issue 36, 34347-34355, September 5, 2003

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Mammals Have Two Twinfilin Isoforms Whose Subcellular Localizations and Tissue Distributions Are Differentially Regulated^*

Maria K. Vartiainen  , Elisa M. Sarkkinen , Tanja Matilainen ¶, Marjo Salminen ¶ and Pekka Lappalainen  ||

From the Programs in Cellular Biotechnology and ^¶Developmental Biology, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland

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 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 (K_D = 0.12 µM) than ATP-G-actin (K_D = 1.96 µM) 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.

Received for publication, April 8, 2003 , and in revised form, June 2, 2003.

^* This study was supported by grants from the Academy of Finland, Biocentrum Helsinki, Sigrid Jusélius Foundation, and the European Molecular Biology Organization (EMBO) Young Investigator Program (to P. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Division of Molecular Cell Biology, School of Biosciences, University of Birmingham, B15–2TT, Birmingham, England.

^|| To whom correspondence should be addressed: Institute of Biotechnology, P. O. Box 56, 00014 University of Helsinki, Finland. Tel.: 358-9-19159499; Fax: 358-9-19159366; E-mail: pekka.lappalainen{at}helsinki.fi.

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