ReviewGuiding cell migration through directed extension and stabilization of pseudopodia
Introduction
Directed cell movement is an essential component of many critical biological processes including embryonic development, wound repair, and immune surveillance. However, deregulated or inappropriate cell migration can contribute to pathological states such as rheumatoid arthritis and tumor cell metastasis. A better understanding of the fundamental mechanisms that impact cell movement is central to improving therapeutics for the pathological conditions associated with defective cell motility. Directed migration (or chemotaxis) is a carefully orchestrated cellular event that is composed of tightly integrated processes for sensing directional cues, protruding membrane structures, and regulating turnover of adhesive contacts with the underlying substratum. Although many cells randomly protrude membrane structures from their surface when in the presence of a uniform concentration of chemoattractant, in response to a chemoattractant gradient, cells rapidly adopt a persistent morphological polarity with extension of a single pseudopodium in the direction of increasing chemoattractant. The initial detection and continual navigation of cells toward chemoattractant are initiated by membrane-associated receptors that convert extracellular chemoattractant concentrations into highly orchestrated internal signaling events. The receptor-generated signals eventually converge in the localized polymerization of F-actin, which is manifested as an asymmetric reorganization of the actin–myosin cytoskeleton. However, the precise mechanisms of coupling and modulation of signals generated from different membrane receptors to the processes regulating pseudopodia extension are not entirely understood. In this review, we highlight recent insights into the molecular mechanisms that establish formation of a dominant pseudopodium in chemotaxis and discuss perspectives of how cells spatially and temporally integrate these mechanisms to maintain persistent polarity and directed cell migration.
Section snippets
Protrusion of a pseudopodium initiates morphological polarity
Cells exposed to a gradient of chemoattractant acquire asymmetric polarity marked by protrusion of membrane structures in the direction of increasing chemoattractant concentration. These protrusive structures can be large, sheet-like lamellipodia, or thin, finger-like filopodia, collectively termed pseudopodia. The pseudopodia region immediately after activation contains a large number of new F-actin filaments [1] and it is now well accepted that pseudopodia protrusion, and more generally,
Distinct cellular mechanisms interpret directional cues
While all living cells can sense their extracellular surroundings, directional sensing requires a cell to spatially integrate nonuniform concentrations of stimuli across its body and locate the direction of increasing concentration. The intriguing capability of cells to spatially detect and internally process external stimuli is a fundamental and necessary step in chemotaxis [15]. In the absence of a cue for directionality, cells move randomly and protrude pseudopodia in multiple directions [16]
Examining protrusion of a dominant pseudopodium
The molecular basis for the formation of a pseudopodium, including regulation of F-actin polymerization, microtubule dynamics, and spatiotemporal regulation of signaling molecules that coordinate these processes, has been under intense investigation. Recent progress has been made studying individual cells responding to a point source of chemoattractant diffusing from a micropipette by tracing the spatiotemporal organization of signals using immunofluorescent technology [18], [19], [20] or
Maintaining polarity and persistent migration
Initially, the polymerization of F-actin plays a critical role in the extension of a pseudopodium as it extends away from the cell body. However, after reaching a maximum extension, the pseudopodium retracts if it is not stabilized by adhering to a supporting substrate, even in the continued presence of a chemoattractant gradient [11]. Upon stabilization of an advancing pseudopodium by attachment, cell movement commences in the direction of increasing concentration of chemoattractant as the
Conclusions and perspectives
Explicating the molecular mechanisms that underlie directed cell migration has proven to be a challenging undertaking, as cell migration is comprised of several complex molecular and cellular processes that are coordinated in both time and space. In response to extracellular cues, cells detect and advance pseudopodia in the direction of movement. The extending pseudopodia adhere to the supporting substrate, providing stable contacts for traction and cell body contraction. The front and back of
Acknowledgments
This work was supported by National Institutes of Health Grant CA97022 (to R.L.K.) and National of Institutes of Health Grant CA75924 (to D.C.). This is paper 16752-IMM from The Scripps Research Institute.
References (41)
- et al.
G protein signaling events are activated at the leading edge of chemotactic cells
Cell
(1998) - et al.
Novel pathways of F-actin polymerization in the human neutrophil
Blood
(2003) - et al.
Regulation of protrusion shape and adhesion to the substratum during chemotactic responses of mammalian carcinoma cells
Exp. Cell Res.
(1998) - et al.
Controlled pseudopod extension of human neutrophils stimulated with different chemoattractants
Biophys. J.
(2004) - et al.
Multiple roles of integrins in cell motility
Exp. Cell Res.
(2000) - et al.
Multiple connections link FAK to cell motility and invasion
Curr. Opin. Genet. Dev.
(2004) - et al.
Eukaryotic chemotaxis: distinctions between directional sensing and polarization
J. Biol. Chem.
(2003) - et al.
Tumor suppressor PTEN mediates sensing of chemoattractant gradients
Cell
(2002) - et al.
Temporal and spatial regulation of chemotaxis
Dev. Cell
(2002) - et al.
Multiple chemotactic factors: fine control or redundancy?
Trends Pharmacol. Sci.
(1999)