The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex

• Published in: Cell communication and signaling 2015-10, Vol.13 (1), p.41-41, Article 41
• Main Authors: Sekino, Saki, Kashiwagi, Yuriko, Kanazawa, Hitoshi, Takada, Kazuki, Baba, Takashi, Sato, Seiichi, Inoue, Hiroki, Kojima, Masaki, Tani, Katsuko
• Format: Article
• Language: English
• Subjects: Actin; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Animals; Binding proteins; Cell Movement; Comparative analysis; Cytoskeletal Proteins - metabolism; Fibronectins; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice; Muscle proteins; NIH 3T3 Cells; Protein binding; Protein Transport; Pseudopodia - metabolism; Tyrosine; Wiskott-Aldrich Syndrome Protein Family - metabolism
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-015-0119-5

Abl interactor (Abi) family proteins play significant roles in actin cytoskeleton organization through participation in the WAVE complex. Mammals possess three Abi proteins: Abi-1, Abi-2, and NESH/Abi-3. Abi-1 and Abi-2 were originally identified as Abl tyrosine kinase-binding proteins. It has been disclosed that Abi-1 acts as a bridge between c-Abl and WAVE2, and c-Abl-mediated WAVE2 phosphorylation promotes actin remodeling. We showed previously that NESH/Abi-3 is present in the WAVE2 complex, but neither binds to c-Abl nor promotes c-Abl-mediated phosphorylation of WAVE2. In this study, we characterized NESH/Abi-3 in more detail, and compared its properties with those of Abi-1 and Abi-2. NESH/Abi-3 was ectopically expressed in NIH3T3 cells, in which Abi-1, but not NESH/Abi-3, is expressed. The expression of NESH/Abi-3 caused degradation of endogenous Abi-1, which led to the formation of a NESH/Abi-3-based WAVE2 complex. When these cells were plated on fibronectin-coated dishes, the translocation of WAVE2 to the plasma membrane was significantly reduced and the formation of peripheral lamellipodial structures was disturbed, suggesting that the NESH/Abi-3-based WAVE2 complex was unable to help produce lamellipodial protrusions. Next, Abi-1, Abi-2, or NESH/Abi-3 was expressed in v-src-transformed NIH3T3 cells. Only in NESH/Abi-3-expressed cells did treatment with an Abl kinase inhibitor, imatinib mesylate, or siRNA-mediated knockdown of c-Abl promote the formation of invadopodia, which are ventral membrane protrusions with extracellular matrix degradation activity. Structural studies showed that a linker region between the proline-rich regions and the Src homology 3 (SH3) domain of Abi-1 is crucial for its interaction with c-Abl and c-Abl-mediated phosphorylation of WAVE2. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based one, and NESH/Abi-3 may be involved in the formation of ventral protrusions under certain conditions.