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  • Review Article
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Chemotaxis: signalling the way forward

Nature Reviews Molecular Cell Biology volume 5, pages 626–634 (2004)Cite this article

Key Points

  • Motile eukaryotic cells such as Dictyostelium discoideum and human neutrophils extend pseudopodia with a typical 1-minute life cycle. In a uniform gradient of chemoattractant, these pseudopodia are formed in random directions.

  • During chemotaxis in a gradient of chemoattractant, the spatial and temporal aspects of the chemoattractant concentration are processed, leading to pseudopod extension at the leading edge, retraction of the uropod at the back of the cell, and suppression of lateral pseudopodia.

  • The chemoattractant binds to seven-transmembrane-spanning serpentine receptors, and activates heterotrimeric G-proteins and small GTP-binding proteins of the Rho/Rac class, which leads to the activation of phosphatidylinositol 3-kinase (PI3K) and guanylyl cyclase.

  • At the leading edge Rho/Rac proteins are activated. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulates here as a result of the activity of PI3K that translocates from the cytosol, whereas the PtdIns(3,4,5)P3-degrading enzyme PTEN (phosphatase and tensin homologue) dissociates from the membrane at the leading edge. Rho/Rac proteins and PtdIns(3,4,5)P3-binding proteins induce actin polymerization and pseudopod formation.

  • At the sides and the back of the cell, myosin filaments are formed, which generate the power to retract the uropod, and also inhibit the formation of pseudopodia at the sides of the cell. In D. discoideum this is mediated predominantly by cyclic GMP, whereas in neutrophils, a Rho kinase induces myosin filaments.

Abstract

During random locomotion, human neutrophils and Dictyostelium discoideum amoebae repeatedly extend and retract cytoplasmic processes. During directed cell migration — chemotaxis — these pseudopodia form predominantly at the leading edge in response to the local accumulation of certain signalling molecules. Concurrent changes in actin and myosin enable the cell to move towards the stimulus. Recent studies are beginning to identify an intricate network of signalling molecules that mediate these processes, and how these molecules become localized in the cell is now becoming clear.

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Figure 1: Chemotaxis involves three interrelated phenomena.
Figure 2: Directional sensing in immobilized cells.
Figure 3: Uniform chemoattractant increments trigger biphasic responses.
Figure 4: Myosin-II filaments in chemotaxis.

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Acknowledgements

The authors wish to thank all the members of their laboratories who have contributed much of the work discussed in this review. P.N.D. is supported by grants from the National Institutes of Health. P.V.H. is supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

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Authors and Affiliations

  1. Department of Biochemistry, University of Groningen, Nijenborgh 4, Groningen, 9747 AG, The Netherlands

    Peter J. M. Van Haastert

  2. Department of Cell Biology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 114 Woods Basic Science Building, Baltimore, 21205, Maryland, USA

    Peter N. Devreotes

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DATABASES

Swiss-Prot

Cdc42

Gαi

Gα2

Gα12

Gα13

PAK1

PI3Kγ

PKB

PREX1

PTEN

ROCK

WASP

Glossary

NEUTROPHIL

A phagocytic cell of the myeloid lineage that has an important role in the inflammatory response. It undergoes chemotaxis towards sites of infection or wounding.

FLAGELLUM

The cell-motility apparatus in swimming bacteria.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to about 1 μm back into the lamellipodium.

UROPOD

A slender appendage that is formed at the trailing, rear edge of fast-migrating cells such as amoebae, neutrophils or lymphocytes.

SEVEN-TRANSMEMBRANE-SPANNING RECEPTOR

A receptor that contains seven membrane-spanning helices and usually transmits signals to the inside of a cell by activating heterotrimeric G proteins.

HETEROTRIMERIC G PROTEIN

A protein complex of three proteins (Gα, Gβ, and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

FRET

(fluorescence resonance energy transfer). A method to identify the proximity of two proteins, each of which is labelled with a different fluorescent group.

PLECKSTRIN-HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

Arp2/3 COMPLEX

A complex that consists of two actin-related proteins, Arp2 and Arp3, along with five smaller proteins. When activated, the Arp2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

RHO-FAMILY GTPases

Ras-related small GTPases that are involved in controlling the polymerization of actin.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR (GEF)

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

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Van Haastert, P., Devreotes, P. Chemotaxis: signalling the way forward. Nat Rev Mol Cell Biol 5, 626–634 (2004). https://doi.org/10.1038/nrm1435

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