Dicing with dogma: de-branching the lamellipodium

Abstract

The primary event in the movement of a migrating eukaryotic cell is the extension of cytoplasmic sheets termed lamellipodia composed of networks of actin filaments. Lamellipodia networks are thought to arise through the branching of new filaments from the sides of old filaments, producing a dendritic array. Recent studies by electron tomography have revealed the three dimensional organization of lamellipodia and show, contrary to previous evidence, that actin filaments do not form dendritic arrays in vivo. These findings signal a reconsideration of the structural basis of protrusion and about the roles of the different actin nucleating and elongating complexes involved in the process.

Figure 1

Proposed tethered nucleation/elongation model of actin network formation in lamellipodia and transitions to filopodia. (a) Based on the results from electron tomography , actin filaments in lamellipodia form un-branched networks that include cross-linked filament pairs that can serve as potential precursors of filopodia. (b) Enlargement of the area boxed in yellow in A. In this hypothetical scheme, actin filaments are nucleated via the interaction of the Arp2/3 complex with the activated WAVE complex on the membrane. The Arp2/3 complex remains at the pointed end of the filament and treadmills with actin. The filament plus end elongates while being tethered to WAVE or to proximal Ena/VASP oligomers after transfer from WAVE. Filaments elongating on VASP can associate in pairs that are stabilized by a short actin cross-linker, like fascin. Long cross-linkers, such as filamin, stabilize the actin network. (c) Enlargement of the area boxed in white in A. Filopodia form via the clustering and bundling of actin filament pairs. At the filopodia tip, Ena/VASP proteins and formins cooperate in filament elongation. The inventory of proteins at lamellipodia and filopodia tips is far from complete; aside from missing adaptors, formins may also be involved in the generation of filament pairs in lamellipodia and one of the WAVE isoforms, WAVE 2, is found at filopodia tips .

Figure I

The dendritic nucleation model.