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Modulation of signalling by Sprouty: a developing story

Key Points

  • Spry is a conserved protein that was originally identified as an antagonist of fibroblast growth factor (FGF)-dependent tracheal development in Drosophila melanogaster and was subsequently shown to function as a general inhibitor of receptor tyrosine kinase (RTK) signalling. Four mammalian homologues (SPRY1, 2, 3 and 4) have been identified, all of which have been implicated in the modulation of RTK signalling.

  • All SPRY proteins have a conserved carboxy-terminal cysteine-rich domain that is necessary for their specific localization and function. The amino terminus of SPRY is divergent except for a conserved tyrosine residue. The sequence divergence of the amino terminus has been suggested to dictate different functions by mediating distinct protein–protein interactions.

  • As an inducible inhibitor of RTK signalling, the expression patterns of SPRY during embryonic development are coincident with known sites of RTK signalling. The widespread dependence of SPRY expression on RTK signalling implies that SPRY participates in negative-feedback control of signalling. The duration of SPRY action is restricted by a post-translational mechanism involving ubiquitylation-dependent proteolytic degradation.

  • SPRY exerts its inhibitory effect on RTK signalling by intercepting essential elements of the RAS–ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) cascade through diverse mechanisms.

  • Unexpectedly, mammalian SPRY proteins were found to potentiate epidermal growth factor (EGF) signalling by sequestering CBL and impairing EGF-receptor ubiquitylation and degradation.

  • SPRY expression has various biological consequences, including regulation of cell proliferation and differentiation, endocytic sorting of activated RTKs, control of cytoplasmic calcium concentrations, the migratory behaviour of cells, lung morphogenesis and bone development.

Abstract

Sprouty proteins are evolutionarily conserved inducible inhibitors of signalling by receptor tyrosine kinases. They have been implicated in negative-feedback interactions that impart spatial and temporal constraints to intracellular signals. The repressive function of Sprouty proteins targets several receptor-tyrosine-kinase-dependent signalling steps, indicating that their activities might have broader biological consequences than was initially anticipated.

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Figure 1: Sprouty and SPRED proteins.
Figure 2: Sprouty interactions.
Figure 3: Repression of RTK signalling by Sprouty.
Figure 4: Sprouty–CBL interaction.
Figure 5: The role of Sprouty in branching morphogenesis during Drosophila melanogaster tracheal development.

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Acknowledgements

We thank our colleagues for helpful comments in the review. We apologize to those authors whose papers could not be cited due to space limitation. The authors are supported by grants from the National Institutes of Health (to D.B.-S) and a Department of Defense predoctoral fellowship (to H.J.K.).

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Correspondence to Dafna Bar-Sagi.

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DATABASES

Flybase

D.m. Spry

Bnl

Btl

Drk

Gap1

Interpro

EVH1

Swiss-Prot

CBL

GRB2

RAF

SHP2

SOS

SPRED1

SPRED2

SPRY1

SPRY2

SPRY4

UBCH7

WT1

Glossary

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

IMAGINAL DISC

A single-cell layer epithelial structure of the D. melanogaster larva that gives rise to wings, legs and other appendages.

MEMBRANE RUFFLE

A process that is formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.

LAMELLIPODIA

A thin, sheet-like cell extension that is found at the leading edge of crawling cells or growth cones.

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.

CAVEOLAE

Specialized rafts that contain the protein caveolin and form flask-shaped, cholesterol-rich invaginations of the plasma membrane that might mediate the uptake of some extracellular materials and are probably involved in cell signalling.

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.

PALMITOYLATION

The covalent attachment of a palmitate (16-carbon, saturated fatty acid) to a cysteine residue through a thioester bond.

EPISTASIS

A description of the relationship between alleles of different genes. Epistasis analysis is often used by geneticists to order genes in a pathway. When an animal that is a double mutant for two different genes displays the phenotype of one of the single mutants and not the other, the gene which is responsible for the observed phenotype is said to be epistatic.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

RING FINGER

A protein domain that consists of two loops that are held together at their base by cysteine and histidine residues that form a complex with two zinc ions. Many RING fingers function in protein degradation by facilitating protein ubiquitylation.

E2 UBIQUITIN-CONJUGATING ENZYME

An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme (E1) and, together with a ubiquitin ligase (E3), transfers it to a substrate protein.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger dense-core granules.

DOMINANT-NEGATIVE

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

CHONDRODYSPLASIA

A general name for heterogenous disorders of skeletal development and growth that involves alterations in the architecture of epiphyseal growth and endochondral ossification.

HELA CELLS

An established tissue-culture strain of human epidermoid carcinoma cells, containing 70–80 chromosomes per cell. These cells were originally derived from tissue taken from a patient named Henrietta Lacks in 1951.

FOCAL-ADHESION COMPLEX

A flat, elongated structure, about 2–5 μm in size, that is found primarily at the cell periphery and mediates adhesion to the substrate by connecting the actin cytoskeleton with the extracellular matrix.

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Kim, H., Bar-Sagi, D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5, 441–450 (2004). https://doi.org/10.1038/nrm1400

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