Cell Migration: Integrating Signals from Front to Back

Abstract

Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.

Cell biology of embryonic migration

“…1) (Lauffenburger and Horwitz, 1996;Pollard and Borisy, 2003;Ridley et al, 2003). The major structures that define the leading edge activity of a migrating cell are lamella, lamellipodia, and filopodia.…”

“…Polarization-In order to move in a certain direction, a cell first needs to polarize in that direction, i.e., to define its front (that will move forward) and its back (that will remain in the rear and retract as the leading edge protrudes). The central regulators of establishing this polarity are Rho family small GTPase Cdc42 (Etienne-Manneville and Hall, 2001;Itoh et al, 2002), Par proteins, and atypical protein kinase (aPKC) (see (Ridley et al, 2003) for overview). Additional signals are provided by a gradient of phosphatidylinositol triphosphate (PIP3) (decreasing from front to rear), produced by the action of phosphoinositide-3 kinase (PI3K), and regulated by PTEN, a PIP3 phosphatase, which is located to the cell rear and controls the lower level of PIP3 at the trailing edge.…”

“…Despite the differences in the cell types that take part in different migratory events, it is believed that all of these migrations occur by similar molecular mechanisms, whose major components have been functionally conserved in evolution for over a billion years, from protozoa to mammals. Molecular mechanisms of migration have been extensively studied over the past decades (see Pollard and Borisy, 2003;Ridley et al, 2003;Vicente-Manzanares et al, 2005 and Cell Migration Gateway http://www.cellmigration.org for overviews). While many mysteries underlying the regulatory mechanisms of migration still remain to be uncovered, significant progress has been made in the mechanistic understanding of migration and the major molecular events that occur inside the cell during directional movement.…”

ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase

“…3 Cells interact with ECM components via heterodimeric cell surface proteins called integrins. 4 ECM-integrin interaction stimulates signal transduction pathways that regulate a number of cellular processes important in cancer growth, including cell cycle transition and protection from apoptosis. 4 We have shown that adhesion of SCLC cells via b1 integrins to ECM components promotes cell survival and confers resistance to chemotherapeutic agents.…”

“…4 ECM-integrin interaction stimulates signal transduction pathways that regulate a number of cellular processes important in cancer growth, including cell cycle transition and protection from apoptosis. 4 We have shown that adhesion of SCLC cells via b1 integrins to ECM components promotes cell survival and confers resistance to chemotherapeutic agents. 3 This has now been demonstrated to be a general mechanism for acquired drug resistance in a number of malignancies including myeloma, breast and colon cancer.…”