Abstract
The regulation of cell migration is a highly complex process that is often compromised when cancer cells become metastatic. The microtubule cytoskeleton is necessary for cell migration, but how microtubules and microtubule-associated proteins regulate multiple pathways promoting cell migration remains unclear. Microtubule plus-end binding proteins (+TIPs) are emerging as important players in many cellular functions, including cell migration. Here we identify a +TIP, GTSE1, that promotes cell migration. GTSE1 accumulates at growing microtubule plus ends through interaction with the EB1+TIP. The EB1-dependent +TIP activity of GTSE1 is required for cell migration, as well as for microtubule-dependent disassembly of focal adhesions. GTSE1 protein levels determine the migratory capacity of both nontransformed and breast cancer cell lines. In breast cancers, increased GTSE1 expression correlates with invasive potential, tumor stage, and time to distant metastasis, suggesting that misregulation of GTSE1 expression could be associated with increased invasive potential.
Highlights
Cancer cells that have become metastatic are defined by an increased motility, and the modulation of molecular pathways controlling cell migration is important for the progression to metastasis [1,2,3,4]
GTSE1 localizes to growing microtubule tips through interaction with the EB1+TIP, and this interaction and localization is required for GTSE1’s role in cell migration, as well as for turnover of focal adhesion complexes
We have identified the EB1-dependent +TIP activity of GTSE1, which is required for its role in cell migration, as required to support microtubule-dependent disassembly of focal adhesions
Summary
Cancer cells that have become metastatic are defined by an increased motility, and the modulation of molecular pathways controlling cell migration is important for the progression to metastasis [1,2,3,4]. MAPs are frequently found overexpressed in tumors, where they are thought to promote cancer progression and resistance to MTtargeting chemotherapy drugs in part by altering microtubule dynamics and stability and promoting chromosomal instability in mitosis [6,7]. Due to their important role in cell motility, misregulation of microtubule functions may potentially contribute to cancer progression through misregulation of cell migration, by promoting tumor cell invasion and metastasis [5], there is less evidence for this to date. To better understand how regulation of microtubule-dependent cell migration affects cancer progression, it is necessary to elucidate the contributions of individual MAPs
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