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  • Review Article
  • Published:

Semaphorins command cells to move

Key Points

  • Semaphorins are secreted or transmembrane proteins that mediate repulsive axon guidance, immune cell regulation, and vascular growth and remodelling.

  • Semaphorins signal through plexins. Plexins, in turn, recruit and regulate kinases and Rho-family GTPases to control cell motility.

  • It has recently been shown that plexins also have intrinsic GAP (GTPase-activating protein) activity towards R-Ras on semaphorin binding. Plexin GAP activity decreases the activity of R-Ras.

  • Active R-Ras promotes integrin-mediated attachment to the extracellular matrix.

  • Semaphorins have been shown in many systems to decrease integrin-mediated attachment. It is now possible to attribute these phenomena to the regulation of R-Ras through plexins.

Abstract

Semaphorins are secreted or transmembrane proteins that regulate cell motility and attachment in axon guidance, vascular growth, immune cell regulation and tumour progression. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.

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Figure 1: Semaphorins and plexins.
Figure 2: Plexin signalling.
Figure 3: Semaphorins repel axonal growth cones.
Figure 4: Dual roles for semaphorins in the vasculature.
Figure 5: Viral semaphorins signal through Plexin-C1.

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DATABASES

Swiss-Prot

CDK5

Plexin-B1

Plexin-B2

Plexin-D1

RhoA

RND1

R-Ras

Sema3A

Sema3B

Sema3F

Sema4D

Sema7A

FURTHER INFORMATION

Kun-Liang Guan's laboratory

Glossary

RHO-FAMILY GTPASES

Ras-related GTPases that are involved in controlling the dynamics of the actin cytoskeleton.

IMMUNOGLOBULIN-LIKE DOMAIN

A protein domain composed of two β pleated sheets held together by a disulphide bond.

THROMBOSPONDIN DOMAIN

A small three-stranded domain of 60 amino acids that has homology to thrombospondin and that is characterized by three conserved disulphide bonds.

PDZ DOMAIN

(Postsynaptic-density protein of 95 kDa, Discs large, Zona occludens-1). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.

CONVERTASE-CLEAVAGE SITES

Sites of post-translational proteolytic cleavage by subtilisin or proteases that regulate the activity of secreted proteins.

GROWTH CONE

The motile tip of growing axons that senses gradients of attractive and repulsive cues to direct motility.

GAPS

Proteins that inactivate small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

ACTOMYOSIN CONTRACTILITY

The process underlying growth cone retraction whereby actin filaments interact with myosin to generate contractile force.

STRESS FIBRES

Also termed 'actin-microfilament bundles', these are bundles of parallel filaments that contain F-actin and other contractile molecules, and often stretch between cell attachments as if under stress.

BILATERIA

A subgroup of animals with bilateral symmetry during development, including worms, flies and humans. These animals have more complex nervous systems than the more distantly related (and radially symmetrical) sponges and jellyfish.

EXTRACELLULAR MATRIX

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

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and therefore competes with normal proteins, thereby impairing normal protein function.

MONOOXYGENASE DOMAIN

A protein domain that catalyses oxidoreduction reactions using a flavin cofactor.

FOCAL ADHESIONS

Integrin-mediated cell–substrate adhesion structures that anchor the ends of actin filaments (stress fibres) and mediate strong attachments to substrates. They also function as an integrin signalling platform.

LAMELLIPODIUM

A fan-shaped membrane extension in growth cones, which is more frequently observed at the edge facing the direction of growth.

RGD SEQUENCE

The primary adhesive motif in many extracellular-matrix molecules, which contains the amino-acid triplet Arg–Gly–Asp.

PLEXUS

A primitive vascular network characterized by a honeycomb appearance and connectivity.

AUTOCRINE

Describing, or relating to, a cell that produces the ligands by which it is activated.

PARACRINE

Describing, or relating to, a regulatory cell that secretes an agonist into intercellular spaces from which it diffuses to a target cell other than the one that produces it.

ANGIOGENESIS

The growth and proliferation of new blood vessels from existing vasculature.

NEURAL CREST CELLS

Cells that originate from the neural crest region of a vertebrate embryo. They migrate outward and are progenitors of mature cell types, including peripheral neurons.

MYOCARDIUM

The muscle wall of the heart.

COMPACT LAYER

The outer layer of the myocardium.

BIDIRECTIONAL SIGNALLING

Occurs when a transmembrane protein stimulates a neighbouring cell as a ligand, and its own cell as a receptor.

POSTSYNAPTIC DENSITY

Higher-order protein structure present in postsynaptic membranes that functions to concentrate neurotransmitter receptors.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein module of 80 amino acids that is present in a range of proteins and was first identified in the protein kinase Src. SH3 domains interact with proline-rich sequences that usually contain a PXXXPXR motif.

TRABECULATION

The process of making ridges in the myocardium, caused by the perpendicular migration of myocardial cells.

POXVIRUSES

A group of enveloped, DNA viruses that can cause pox diseases in vertebrates.

MONOCYTES

Large leukocytes with a horseshoe-shaped nucleus. They derive from pluripotent stem cells and become phagocytic macrophages when they enter the tissues.

DENDRITIC CELLS

Sentries of the immune system named for their extensive membrane extensions. They ingest antigens by phagocytosis, degrade them and present them to T cells as part of the adaptive immune response.

PHAGOCYTOSIS

An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.

ANTIGEN-PRESENTING CELL

A cell, most often a macrophage or dendritic cell, that presents an antigen to activate a T cell.

MAJOR HISTOCOMPATIBILITY COMPLEX

A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self.

LOSS OF HETEROZYGOSITY

Deletion or disruption of one of two copies of a gene.

METASTASIS

The movement of cancerous cells from one area of the body to another.

FASCICULATION

The bundling of axons.

OLIGODENDROCYTE

A supporting cell in the nervous system that forms a myelin sheath around axons.

EXTRAVASATION

The process of cancer- and immune-cell migration across the blood vessel endothelial layer into surrounding tissues.

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Kruger, R., Aurandt, J. & Guan, KL. Semaphorins command cells to move. Nat Rev Mol Cell Biol 6, 789–800 (2005). https://doi.org/10.1038/nrm1740

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