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- Title
Macromolecular complexes in invadopodia formation.
- Authors
Kropyvko, Sergii; Gryaznova, Tetyana; Gubar, Olga; Kryklyva, Valentyna; Burdyniuk, Mariia; Dergai, Mykola; Tsyba, Liudmyla; Vassetzky, Yegor; Rynditch, Alla
- Abstract
Aim. Invasive cancer cells form membrane protrusions, invadopodia, that degrade extracellular matrix and facilitate cell invasion and metastasis. Invadopodia contain an actin-rich core surrounding by adhesion and scaffolding proteins which presence correlates with invasive behavior of human cancer cells. Key players include the adaptor proteins Tks4 and Tks5, the actin regulators cortactin and N-WASP, the tyrosine kinase Src and the transmembrane metalloprotease MT1-MMP. In spite that in the last two decades significant advances in our knowledge of the structure and development of invadopodia have been made, detailed mechanisms by which they facilitate cell migration is not yet available. Methods. We used pull-down assay and Wester blot analysis, immunofluorescence and confocal microscopy, invadopodia gelatin degradation assay. Results. We have identified a series of new Tks4 binding partners including adaptor proteins of the ITSN family (ITSN1 and ITSN2) and small adaptor molecules Crk and Grb2, the Amphiphysin protein family (Amph1 τa Amph2), kinase Src and phospholipase C gamma 1 (PLCg1) and also another member of the Tks family - Tks5. It may indicate the possible role of Tks4 in transport and sorting of cell vesicles. Current data is supported by interaction with the proteins of Amphiphysin family (Amph1 τa Amph2), as their main functions are membrane trafficking and remodeling. Adaptor proteins Crk, Grb2 and ITSNs are important for the actin cytoskeleton rearrangements and signal transduction. Tks4 also may participate in these processes as we found that Tks4 formes complexes with above mentioned proteins. Moreover, we have identified and characterized new Tks4 isoform - Tks4-beta. We suggested that an active state of Tks4 is regulated via intramolecular interactions between its proline-rich motifs and own SH3-domains. We have shown the interaction between ITSNs and other prominent component of invadopodia WIP. Data from immunofluorescent analysis revealed co-localization of ITSN1 and WIP at the sites of invadopodia formation and in clathrin-coated pits. We have also demonstrated that the key endocytic protein ITSN1 and WIP and N-WASP can form a complex in cells. Together, these findings provide insights into the molecular mechanisms of invadopodia formation and identify ITSNs as scaffold proteins involved in this process.
- Publication
Biopolymers & Cell, 2015, p25
- ISSN
0233-7657
- Publication type
Academic Journal