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.
Highlights
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]
TIP150-Cortactin Interaction Orchestrates Cell Migration complexes are initiated outside of the cell by binding to the extracellular matrix, where they mechanically connect the extracellular matrix to the actin cytoskeleton and provide the anchor points required for cell migration [1, 10, 11]
Microtubule plus end tracking proteins constitute a complex structural platform that orchestrates the molecular events involved in regulating microtubule dynamics required for cell
Summary
Cortactin (CTN) 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]. The cytoskeletal interactions controlling cell migration are mediated by mechanisms that promote dynamic regulation of microtubule-associated proteins (MAPs) [9]. Previous studies suggest that MAP-dependent regulatory pathways control cell migration by stimulating actin polymerization at the leading edge of migrating cells and, through the modulation of dynamic cell adhesion properties, regulate both the stabilization and disassembly of focal adhesion complexes [10]. TIP150-Cortactin Interaction Orchestrates Cell Migration complexes are initiated outside of the cell by binding to the extracellular matrix, where they mechanically connect the extracellular matrix to the actin cytoskeleton and provide the anchor points required for cell migration [1, 10, 11]. We identify that TIP150 directly associates with the actin-binding protein, CTN, via its C-terminal proline-rich region (CT150). Our study suggested that the TIP150-CTN interaction orchestrates directional cell migration via linking dynamic microtubule plus ends to the cortical cytoskeleton
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