The Microtubule Plus End Tracking Protein TIP150 Interacts with Cortactin to Steer Directional Cell Migration

Abstract

Cell migration is orchestrated by dynamic interactions of microtubules with the plasma membrane cortex. How these interactions facilitate these dynamic processes is still being actively investigated. TIP150 is a newly characterized microtubule plus end tracking protein essential for mitosis and entosis (Ward, T., Wang, M., Liu, X., Wang, Z., Xia, P., Chu, Y., Wang, X., Liu, L., Jiang, K., Yu, H., Yan, M., Wang, J., Hill, D. L., Huang, Y., Zhu, T., and Yao, X. (2013) Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis. J. Biol. Chem. 288, 15771-15785; Xia, P., Zhou, J., Song, X., Wu, B., Liu, X., Li, D., Zhang, S., Wang, Z., Yu, H., Ward, T., Zhang, J., Li, Y., Wang, X., Chen, Y., Guo, Z., and Yao, X. (2014) Aurora A orchestrates entosis by regulating a dynamic MCAK-TIP150 interaction. J. Mol. Cell Biol. 6, 240 -254). Here we show that TIP150 links dynamic microtubules to steer cell migration by interacting with cortactin. Mechanistically, TIP150 binds to cortactin via its C-terminal tail. Interestingly, the C-terminal TIP150 proline-rich region (CT150) binds to the Src homology 3 domain of cortactin specifically, and such an interaction is negatively regulated by EGF-elicited tyrosine phosphorylation of cortactin. Importantly, suppression of TIP150 or overexpression of phospho-mimicking cortactin inhibits polarized cell migration. In addition, CT150 disrupts the biochemical interaction between TIP150 and cortactin in vitro, and perturbation of the TIP150-cortactin interaction in vivo using a membrane-permeable TAT-CT150 peptide results in an inhibition of directional cell migration. We reason that a dynamic TIP150-cortactin interaction orchestrates directional cell migration via coupling dynamic microtubule plus ends to the cortical cytoskeleton.Cell migration is an essential physiological function that is tightly regulated in numerous biological processes, including development, tissue remodeling, wound healing, and tumor metastasis (1, 2). These processes require coordination of dynamic reorganization between the actin filaments and microtubules.Cortactin (CTN) 6 is a multidomain-containing scaffold protein that consists of an N-terminal acidic domain, six and a half tandem repeats, an ␣ helix, a proline-rich region, and an Src Homology (SH3) domain at its C terminus (3). CTN is an important scaffold for promoting the polymerization and rearrangement of the actin cytoskeleton (4). Functionally, CTN, distributed at protrusions and the leading edges, is necessary for cell migration by regulating intercellular adhesion and cell spreading (5). Importantly, CTN is phosphorylated at tyrosine residues in response to growth factor receptors, which regulates cell migration (6).Microtubules, one of the three major components of the cytoskeleton, are required for maintaining the physical and plastic properties of migrating cells (7). The plus en...

Single-cell transcriptome analysis during cardiogenesis reveals basis for organ level developmental anomalies

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Non-equilibrium assembly of microtubules: from molecules to autonomous chemical robots

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Viriditoxin Stabilizes Microtubule Polymers in SK-OV-3 Cells and Exhibits Antimitotic and Antimetastatic Potential

“…Coordination of dynamic reorganization between the actin filaments and microtubules is essential for cell migration. As one of the components of the cytoskeleton, microtubules are required for maintaining the physical and plastic properties of migrating cells and for both directional and random movements [21]. Tumor metastasis stems from cancer cell migration and colony formation (clonogenicity) [21,22].…”

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“…Concentration-response measurements further revealed that viriditoxin inhibited cell migration at low concentrations ( Figure 7B). cancer cell migration and colony formation (clonogenicity) [21,22]. Therefore, we analyzed the effects of the microtubule inhibitor viriditoxin on the migratory and clonogenic properties of SK-OV-3 cells.…”