Building new connections

Cells are crisscrossed by microtubules, protein cables that provide infrastructure, which facilitate cellular migration and assist in transport of molecular cargo, among other functions.

Most microtubules radiate out from structures known as centrosomes, but many cells also contain non-centrosomal microtubules of ambiguous function that are anchored to yet-unknown cellular targets.

For example, in epithelia—cell sheets that compose tissues including the skin and digestive tract—evidence has suggested that microtubules may interact with adherens junctions (AJs), protein complexes that connect epithelial cells together. “However, it was not clearly understood whether and how microtubules were involved in AJ formation,” says Masatoshi Takeichi, of the RIKEN Center for Developmental Biology in Kobe.

Fortunately, a new study by Takeichi’s team, including lead author Wenxiang Meng, offers some illumination. The researchers were looking for interacting partners for p120-catenin, a protein that participates in formation of the zonula adherens (ZA)—bands of AJs that encircle epithelial cells, reinforcing their shape and linking them tightly into two-dimensional sheets.

Their search led to the identification of PLEKHA7 and Nezha, two novel proteins that appear to provide the ‘missing link’ between the ZA and the microtubule network1. Nezha binds to PLEKHA7, which interacts directly with p120, and both Nezha and PLEKHA7 localize to the ZA, where they appear to play an important role in maintaining its integrity.

Meng and Takeichi subsequently found that Nezha interacts directly with non-centrosomal microtubules. Every microtubule has a defined ‘minus’ and ‘plus’ end, with fiber growth occurring exclusively taking place at the latter. Nezha binds specifically to microtubule minus ends, enabling further extension at the plus end, and this association seems to play an essential part in enabling PLEKHA7-Nezha stabilization of the ZA.

Although the details of microtubule involvement in the ZA are still unclear, the researchers uncovered a promising lead when they identified a motor protein, KIFC3, which travels along microtubules towards PLEKHA7-Nezha-associated junctions. “Minus-end directed motors like KIFC3 may utilize these microtubules as a ‘rail’ to transport cargo necessary to maintain the ZA,” says Takeichi.

These findings raise many new questions, but also represent major progress in cell biology, confirming the involvement of microtubules in maintenance of cell-cell junctions and revealing factors that help mediate this function. “To my knowledge, Nezha is the first non-centrosomal protein shown to tether the microtubule minus-ends,” says Takeichi. “These findings are thus a breakthrough for our deeper understanding of the dynamics and biological roles of non-centrosomal microtubules.”

Reference

1. Meng, W., Mushika, Y., Ichii, T. & Takeichi, M. Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts. Cell 135, 948–959 (2008).

The corresponding author for this highlight is based at the RIKEN Laboratory for Cell Adhesion and Tissue Patterning