Abstract
BackgroundTight spatio-temporal signaling of cytoskeletal and adhesion dynamics is required for localized membrane protrusion that drives directed cell migration. Different ensembles of proteins are therefore likely to get recruited and phosphorylated in membrane protrusions in response to specific cues.ResultsHere, we use an assay that allows to biochemically purify extending protrusions of cells migrating in response to three prototypical receptors: integrins, recepor tyrosine kinases and G-coupled protein receptors. Using quantitative proteomics and phospho-proteomics approaches, we provide evidence for the existence of cue-specific, spatially distinct protein networks in the different cell migration modes.ConclusionsThe integrated analysis of the large-scale experimental data with protein information from databases allows us to understand some emergent properties of spatial regulation of signaling during cell migration. This provides the cell migration community with a large-scale view of the distribution of proteins and phospho-proteins regulating directed cell migration.
Highlights
Tight spatio-temporal signaling of cytoskeletal and adhesion dynamics is required for localized membrane protrusion that drives directed cell migration
In this study, we provide for the first time large-scale information about the spatial organization of proteins and phospho-proteins during three different modes of directed cell migration, that involve signaling through distinct prototypical receptors systems: integrins, receptor tyrosine kinase (RTK) and G-coupled protein receptors (GPCR)
Beyond providing spatial information, our approach is very effective at producing robust signaling responses: 1. the response to extracellular matrix (ECM) or chemokine gradients is likely to trigger amplification mechanisms leading to strong signaling responses; 2. the synchronization of membrane protrusion in a specific morphodynamic state leads to a homogeneous signaling state across the cell population
Summary
Tight spatio-temporal signaling of cytoskeletal and adhesion dynamics is required for localized membrane protrusion that drives directed cell migration. Cells respond by polymerizing actin to deform the membrane, enabling to extend local protrusions, which are stabilized through adhesive contacts with the extracellular matrix towards the attractive stimulus [6,7] This membrane protrusion process depends on microtubule dynamics [8], as well as membrane trafficking [9], allowing regulation of membrane remodelling. Because directed membrane protrusion necessitates exquisite crosstalk between actin, adhesion, microtubule and trafficking dynamics, it is reasonable to assume that this process involves precise spatio-temporal regulation of whole signaling networks. This hypothesis prompted us to compare the pool of proteins of the protrusion with the pool of proteins from the cell-body (Figure 1A). By providing comprehensive lists of proteins that localize to specific subcellular compartments, these approaches allow for an integrated view of spatio-temporal signaling networks that underlie cell migration and neuronal differentiation
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