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Coordinating ERK/MAPK signalling through scaffolds and inhibitors

Key Points

  • The Ras–Raf–MEK–ERK/MAPK (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase) pathway mediates many different biological responses. It is still unclear how response fidelity and specificity are determined, although modulations of signal amplitude and duration, spatial constraints, as well as crosstalk with other pathways, have important roles.

  • This pivotal regulation is mainly afforded through the manipulation of protein interactions by scaffolding, inhibitor and adaptor proteins that enhance, decrease or redirect the signal flux.

  • Examples of signalling enhancers are scaffolding proteins such as kinase suppressor of Ras-1 (KSR1) and MEK partner-1 (MP1), which tether components together ensuring a fast and selective response.

  • Inhibitors, such as Raf kinase inhibitor protein (RKIP), selectively disrupt the interaction between components of signalling pathways adding an additional dimension of regulation.

  • Multidomain adaptor proteins, such as connector enhancer of KSR (CNK), integrate and distribute signals by engaging multiple signalling pathways.

  • The combinatorial interplay between signalling proteins and pathways generates a rich diversity of regulation that can influence specific biochemical and biological responses. Unravelling these networks is an important challenge, which is facilitated by computational modelling.

Abstract

The pathway from Ras through Raf and MEK (MAPK and ERK kinase) to ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) regulates many fundamental cellular processes. Recently, a number of scaffolding proteins and endogenous inhibitors have been identified, and their important roles in regulating signalling through this pathway are now emerging. Some scaffolds augment the signal flux, but also mediate crosstalk with other pathways; certain adaptors target MEK–ERK/MAPK complexes to subcellular localizations; others provide regulated inhibition. Computational modelling indicates that, together, these modulators can determine the dynamic biological behaviour of the pathway.

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Figure 1: KSR and Raf domains.
Figure 2: The KSR regulation cycle.
Figure 3: CNK interaction partners and signalling targets.
Figure 4: Paxillin connects the ERK/MAPK and FAK pathways.
Figure 5: MORG1 and MP1.
Figure 6: RKIP and ERK/MAPK activation.

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Acknowledgements

I thank members of my laboratory for helpful discussions and apologize to all the authors whose work could not be cited because of space restriction.

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DATABASES

Swiss-Prot

A-Raf

B-Raf

β-arrestin-1

β-arrestin-2

CNK1

CNK2

EGF

FAK

Grb2

GRK2

HGF

IMP

KSR1

MEK

MP1

paxillin

PEA15

Raf-1

Ras

RASSF1

RhoA

RhoB

RhoC

RKIP

FURTHER INFORMATION

Walter Kolch's Laboratory

Glossary

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells which is used as model for neuronal differentiation as the cells 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.

ACTIVATION LOOP

A 20–25-residue segment in a protein kinase that functions to modulate kinase activity.

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.

14-3-3 PROTEINS

A large class of proteins that are involved in cell division, apoptosis, signal transduction, transmitter release, receptor function, gene expression and enzyme activation in eukaryotes. They function by binding to a wide range of specific target proteins, usually in response to phosphorylation of these targets.

E3 UBIQUITIN LIGASE

The final enzyme complex in the ubiquitin-conjugation pathway. E3 enzymes transfer ubiquitin from previous components of the pathway to the substrate protein to form a covalently linked ubiquitin–substrate conjugate.

DOMINANT NEGATIVE

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

STERILE α-MOTIF

(SAM). Domain of 70 amino acids roughly conserved in many proteins and thought to participate in protein–protein interactions.

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.

PLECKSTRIN-HOMOLOGY (PH) DOMAIN

A protein module of 100 amino acids that is present in a range of proteins. Different PH domains interact with various phospholipids and are involved in the targeting of the proteins.

EPISTASIS ANALYSIS

Epistasis is the masking of a phenotype caused by a mutation in one gene by a mutation in another gene. Epistasis analysis can therefore be used to dissect the order in which genes in a genetic pathway function.

SH2 DOMAIN

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

SH3 DOMAIN

(Src-homology-3). A protein sequence of 50 amino acids that recognizes and binds sequences that are rich in proline.

FILOPODIA

Thin, transient actin protrusions that extend out from the cell surface and are formed by the elongation of bundled actin filaments in its core.

NUCLEOPORINS

Protein subunits of the nuclear pore complex.

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and GTP-hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

CLATHRIN-COATED PIT

(CCP). The initial site of invagination of a clathrin-coated vesicle.

EARLY ENDOSOME

An intracellular vesicular structure that is a precursor of the mature endosome and that has an important role in endocytosis.

HETEROTRIMERIC G PROTEIN

A protein complex of three proteins (Gα, Gβ and Gγ). Gβ and Gγ form a tight complex, and Gα is part of this 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.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

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

FOCAL ADHESION

An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin signalling platform.

RHO-FAMILY GTPASE

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

LAMELLIPODIA

Flattened, sheet-like structures — which are composed of a crosslinked F-actin meshwork — that project from the surface of a cell. They are often associated with cell migration.

LEADING EDGE

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

LATE ENDOSOMES

These organelles mature from early endosomes and feature lower pH and different protein composition. They usually deliver cargo proteins to lysosomes for degradation.

SHORT INTERFERING RNA

A non-coding RNA (21 nucleotides) that is processed from longer double stranded RNA during RNA interference. Such non-coding RNAs hybridize with mRNA targets, and confer target specificity to the silencing complexes that contain them.

WD40 DOMAIN

A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with Trp-Asp (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each 'blade' is a four-stranded β-sheet. This domain is found in proteins that have different functions.

PHORBOL ESTER

A polycyclic ester that is isolated from croton oil. The most common are phorbol-12-myristate-13-acetate (PMA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). These are potent inflammatory agents and tumour promoters because they mimic diacylglycerol, and thereby cause sustained activation of protein kinase C.

KERATINOCYTE

An epithelial cell of the skin that has differentiated to produce keratin. Keratinocytes are the predominant cell type in the epidermis of the skin.

EVH1 DOMAIN

The Enabled/VASP homology domain-1 is a 110 amino acid sequence that — similarly to SH3 domains — interacts with polyproline-rich regions. Structurally, EVH1 is similar to the PH domain despite low sequence homology and different binding partners.

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Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6, 827–837 (2005). https://doi.org/10.1038/nrm1743

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