Plectin is a major cytoskeleton crosslinking protein that binds to actin, intermediate filaments and microtubules, but also functions as a scaffold for proteins involved in cellular signalling. Now in JCB, Wiche and colleagues report that plectin not only regulates the organization and dynamics of keratin intermediate filaments (IF) but also modulates MAPK signalling during cell migration.

Using electron microscopy, the authors show that keratinocytes from plectin^-/- mice have a looser keratin network that extends further into the periphery than wild-type cells. Expression of plectin1a rescued this phenotype, indicating that plectin is a major organizing element of the IF cytoskeleton. No gross differences were observed in the organization of actin filaments or microtubules.

Plectin-deficient cells shrink more rapidly than wild-type cells in response to changes in osmolarity. This effect was associated with reduced keratin attachment to integrin clusters. Plectin^-/- cells also exhibited faster keratin filament disassembly upon exposure to okadaic acid (which selectively disrupts IF), and higher basal activity of Erk1/2, a MAP kinase that positively regulates keratinocyte migration. These findings prompted the authors to examine the behaviour of plectin-deficient cells in wound healing assays. As they predicted, plectin^-/- cells migrated faster than controls.

The precise mechanism through which plectin regulates the activity of Erk1/2 remains elusive, but the authors suggest that it could result from plectin's interaction with the PKC receptor RACK1. Previous studies have shown that plectin downregulates PKC signalling by sequestering RACK1. Indeed, in the absence of plectin an increase of active PKC and c-Src, an upstream kinase of Erk1/2, was observed in membrane fractions. Conversely, overexpression of RACK1 in wild-type keratinocytes increased their migration velocity to rates comparable with plectin-deficient cells.

This study reveals for the first time the effects of plectin on the organisation and dynamics of intermediate filaments, but more importantly it highlights its function as a scaffolding molecule during migration. By maintaining the stability of IF and sequestering proteins that are important for migration, plectin keeps cell motility under control.

Author: Monica Hoyos-Flight