PMC

Cell migration and membrane protrusions in different environments. Cells migrating on 2D substrates form membrane protrusions called filopodia and lamellipodia at the leading edge. Cells entering into and migrating in a dense rigid ECM in 3D, such as tumor cells on top of a thick ECM and those found around blood vessels, need to form membrane protrusions at the invading front, such as invadopodia and podosomes that have an ECM remodeling activity. Formation of these structures is driven by localized actin polymerization. Proteins involved in formation of these protrusions are often upregulated in malignant cancer cells and associated with increased cell motility and invasion. Arrows indicate the direction of cell migration.

Model for lamellipodium and invadopodium/podosome formation. (A) 1: Unstimulated cells have non-polarized cell morphology in which molecular machinery for barbed end formation including cofilin is inactive. 2: Chemoattractant stimulation induces local activation of cofilin at the leading edge, which leads to severing of pre-existing actin filaments and formation of free barbed ends from which new actin filaments are assembled. This initiates membrane protrusions and sets the direction of cell migration. 3: Arp2/3 complex and WAVEs associate with newly formed actin filaments and induce formation of further barbed ends and the branched actin network. Subsequently, the branched actin filaments are stabilized by cortactin. This strengthens the protrusive force of lamellipodia and leads to cell movement. (B) 1: Invadopodium/podosome formation is triggered by N-WASP/WASP, Arp2/3 complex and cortactin, probably by coupled activation of growth factor receptor and integrin signaling. 2: This precursor is stabilized by further recruitment of invadopodium/podosome components and formation of actin network by cofilin. 3: Anchored precursor then gathers matrix-degrading proteinases to degrade ECM and protrude into matrix. N-WASP/Arp2/3 complex, cortactin, and cofilin continue to induce actin polymerization to maintain the structural core. In contrast to lamellipodia, the structure and organization of actin filaments are not yet determined in invadopodia/podosomes. (C) The signaling pathways leading to protrusion of lamellipodia and invadopodia/podosomes in response to growth factor stimulation. Molecules discussed in this review are highlighted in red.