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Phosphatases in cell–matrix adhesion and migration

Nature Reviews Molecular Cell Biology volume 4, pages 700–711 (2003)Cite this article

Key Points

  • Phosphatases can be classified into two families — the tyrosine phosphatases and the serine/threonine phosphatases — that differ in structure, enzymatic mechanism and regulation.

  • Phosphatases dephosphorylate proteins on tyrosine, threonine and serine residues to influence protein folding, enzymatic activity and protein–protein interactions.

  • Phosphatases affect all components of the migration process including: protrusion of lamellipodia that is induced by remodelling of the actin cytoskeleton and regulated by small GTPase molecular switches; modulation of the dynamics of matrix-adhesion interaction; actin contraction; rear release; and regulation of migratory directionality.

  • Phosphatase activity can either inhibit or stimulate the processes of cell adhesion and migration; phosphatases can also influence signalling-pathway selection by dephosphorylation of specific sites on signal-transduction proteins.

  • Phosphatases have essential roles during embryonic development and in the adult through the regulation of cell–matrix adhesion and migration in diverse cell types.

  • Application of new technologies for the examination of spatio–temporal regulation of phosphatases, as well as for substrate identification, will provide opportunities to further our understanding of the role of phosphatases in adhesion and migration.

Abstract

Many proteins that have been implicated in cell–matrix adhesion and cell migration are phosphorylated, which regulates their folding, enzymatic activities and protein–protein interactions. Although modulation of cell motility by kinases is well known, increasing evidence confirms that phosphatases are essential at each stage of the migration process. Phosphatases can control the formation and maintenance of the actin cytoskeleton, regulate small GTPase molecular switches, and modulate the dynamics of matrix–adhesion interaction, actin contraction, rear release and migratory directionality.

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Figure 1: Influence of phosphatases on cell migration.
Figure 2: Phosphatases regulate the activity of Rho-family GTPases.
Figure 3: FAK activity in integrin complexes is modulated by many phosphatases.
Figure 4: Effects of PTEN and other phosphatases on migration and directionality.

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Acknowledgements

We regret that we were able to review only a portion of the extensive work in this field due to length constraints. M.L. is supported by a National Insitutes of Health grant for postdoctoral fellows. M.L.T. is a Scientist of the Canadian Institutes of Health Research.

Author information

Authors and Affiliations

  1. Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30/Room 421, 30 Convent Drive, MSC 4370, Bethesda, 20892-4370, Maryland, USA

    Melinda Larsen & Kenneth M. Yamada

  2. McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Quebec, Canada

    Michel L. Tremblay

Authors
  1. Melinda Larsen
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  2. Michel L. Tremblay
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  3. Kenneth M. Yamada
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Correspondence to Melinda Larsen or Michel L. Tremblay.

Related links

Related links

DATABASES

Flybase

Slingshot

Interpro

ADF

B′

phosphatases

PP

PTP

SH2

LocusLink

LMW-PTP

PTEN

PTP-PEST

SHP2

Swiss-Prot

FAK

LIMK

POPX1

POPX2

PP1

PP2A

PTP1B

PTPα

PTPδ

PTPσ

PTPφ

SHIP

SHPS1

FURTHER INFORMATION

Kinases

Kinases

Migration

Phosphatases

PPs

PPs

PTPs

PTPs

SHIPs

Glossary

LAMELLIPODIUM

A thin, flat extension at the cell periphery that is filled with a branching meshwork of actin filaments.

LEADING EDGE

The leading, or foremost, region of a motile cell.

FILOPODIA

Thin protrusions from cells that are usually supported by microfilaments.

RHO FAMILY OF SMALL GTPASES

A family of monomeric G proteins that comprises isoforms of Rho, Rac and Cdc42. These are important molecular switches and they control cytoskeletal assembly and contraction.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold upon which tissues are organized, it provides cellular microenvironments and it regulates a variety of cellular functions.

FOCAL COMPLEX

A cell–substrate adhesion structure that mediates initial cell adhesion. Formation of the structure is promoted by Rac, and it can mature to form a focal adhesion.

FOCAL ADHESION

A cell-to-substrate adhesion structure that anchors the ends of actin microfilaments (stress fibres) and mediates strong attachment to substrates.

ACTIN CYTOSKELETON

A cytoplasmic structural framework within cells that is composed of F-actin and associated molecules.

INTEGRINS

A group of heterodimeric, transmembrane adhesion receptors for extracellular-matrix proteins such as fibronectin and vitronectin.

STRESS FIBRE

Also termed an 'actin microfilament bundle'. A bundle of parallel filaments that contains F-actin and other contractile molecules, which often stretches between cell attachments as if under stress.

RAFT

A discrete detergent-insoluble, glycosphingolipid-, sphingomyelin- and cholesterol-enriched domain within cellular membranes, where certain signalling lipids and transmembrane proteins that are involved in signalling are thought to be concentrated.

REACTIVE OXYGEN SPECIES

(ROS). Oxygen molecules, containing an unpaired electron in their outermost shell of electrons in an extremely unstable configuration, which quickly react with another molecule to achieve a stable configuration.

3D-MATRIX ADHESION

A long, thin cell–extracellular-matrix adhesion structure that contains the α5β1 integrin, which is characteristically formed at cell attachments to 3-dimensional, fibronectin-rich extracellular fibrils.

FIBRILLAR ADHESION

An elongated cell–extracellular-matrix adhesion structure that contains the α5β1 integrin, tensin and fibronectin, and that seems to generate fibronectin fibrils using directed translocation of integrins and cellular contractility.

PODOSOME

A circular cell–substrate adhesion structure that contains integrins and associated proteins such as gelsolin and cortactin, which surround a dense core of actin.

HOLOENZYME

An enzyme that consists of more than one subunit, each usually carrying out a different function and often existing as more than one isoform.

CHEMOTAXIS

A type of migration that is stimulated by a gradient of a chemical stimulant or chemoattractant.

ADHERENS JUNCTIONS

Specialized cell–cell adhesions found in epithelium, which contain transmembrane E-cadherin that connects with the cytoskeleton.

EPITHELIAL–MESENCHYMAL TRANSITION

(EMT). A transition of epithelial cells to a migratory phenotype that is more typical of mesenchymal cells. EMT is characterized by loss of adherens junctions and desmosomes with the acquisition of cell–matrix adhesions, and is necessary at many stages of embryonic development.

AXONAL PATHFINDING

The process by which extending nerve fibres find their way to destinations.

DORSAL CLOSURE

A process during Drosophila development in which two epithelial sheets converge, in a coordinated fashion, to close the embryo.

PRIMITIVE STREAK

The site of migration of the mesoderm and definitive endoderm cells from the exterior to the interior of the embryo during gastrulation. It defines the axes of the developing embryo.

GASTRULATION

The process during embryonic development that transforms a blastula into a gastrula and generates the embryonic cell layers: ectoderm, endoderm and mesoderm.

APICAL ECTODERMAL RIDGE

(AER). A region of ectoderm at the distal tip of a limb-bud that is induced by the underlying mesenchyme and is required for sustained outgrowth of the limb.

SUBSTRATE-TRAPPING MUTANT

A phosphatase containing a mutation that allows it to bind to and dephosphorylate a substrate, but not to release it. These are useful tools that allow the transient association of phosphatases and their substrates to be 'frozen' and so more easily detected.

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Larsen, M., Tremblay, M. & Yamada, K. Phosphatases in cell–matrix adhesion and migration. Nat Rev Mol Cell Biol 4, 700–711 (2003). https://doi.org/10.1038/nrm1199

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