Journal Article

Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration

Logue, Jeremy S, Baird, Michelle A, Chadwick, Richard S, Waterman, Clare M, Cartagena-Rivera, Alexander X, Davidson, Michael W

2015

Overview

Within the confines of tissues, cancer cells can use blebs to migrate. Eps8 is an actin bundling and capping protein whose capping activity is inhibited by Erk, a key MAP kinase that is activated by oncogenic signaling. We tested the hypothesis that Eps8 acts as an Erk effector to modulate actin cortex mechanics and thereby mediate bleb-based migration of cancer cells. Cells confined in a non-adhesive environment migrate in the direction of a very large ‘leader bleb.’ Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation. Eps8 capping and bundling activities act antagonistically to organize actin within leader blebs, and Erk mediates this effect. An Erk biosensor reveals concentrated kinase activity within leader blebs. Bleb contents are trapped by the narrow neck that separates the leader bleb from the cell body. Thus, Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement. Cells within an animal have to be able to move both during development and later stages of life. For example, white blood cells have to move around the body and into tissues to fight off infections. Normally, cell movement is heavily controlled and will only happen when it is necessary to keep an animal healthy. However, cancer cells can bypass these controls and ‘metastasize’, or spread to new sites in the body. Cells can move in several different ways: on the one hand, cells can use ‘mesenchymal’ movement, in which the skeleton-like scaffolding of molecules within a cell rearranges to push the cell forward. On the other hand, cells can employ ‘amoeboid’ movement, in which they squeeze their way forward by building up pressure in the cell. Although these different types of movement are only used by some healthy cells and not others, cancer cells can switch between the two. How they do this is still unclear, but now Logue et al. have studied this question using several microscopy techniques. Logue et al. watched skin cancer (or melanoma) cells migrating between a glass plate and a slab of agar, which mimics the confined spaces that cancer cells have to move through within the body. The images showed that the cancer cells formed so-called ‘leader blebs’, finger-like projections that put cells on the right track. The experiments revealed that a protein called Eps8 was responsible for making the skin cancer cells move in this amoeboid fashion. The ‘blebbing’ caused by Eps8 is turned on by another protein called Erk that is often overactive in melanoma cells. Furthermore, Erk can accumulate near and within the cell blebs and this leads to the increased movement of the skin cancer cells. Studying cell movement in melanoma is particularly important because it is the metastatic tumors that kill patients. Therefore, increasing our basic understanding of how cells migrate could eventually lead to better treatment options that stop cancer cells from spreading.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Actin / Actins - metabolism / Adaptor Proteins, Signal Transducing - metabolism / adhesion-independent cell migration / Biosensors / bleb / Cancer / cancer cell biology / Cell adhesion / Cell adhesion & migration / Cell Biology / Cell body / Cell Line, Tumor / Cell Movement / Cytoskeleton / Epidermal growth factor / Eps8 / Erk / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / Humans / Kinases / MAP kinase / Mechanical properties / Melanoma / Mutation / Neck / Phosphorylation / Polymerization / Proteins