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Signalling

Mixed-lineage kinase control of JNK and p38 MAPK pathways

Key Points

  • Mixed-lineage kinases (MLKs) are serine/threonine-directed protein kinases.

  • The MLK family consists of nine members in the human genome that belong to three subfamilies — MLK, dual-leucine-zipper-bearing kinase (DLK) and zipper sterile-α-motif kinase (ZAK).

  • MLKs are members of mitogen-activated-protein kinase (MAPK) modules that contain c-Jun amino-terminal kinase (JNKs) or p38 MAPKs.

  • MLKs bind the scaffold-like JNK-interacting proteins (JIPs).

  • The Drosophila MLK Slipper regulates epithelial-cell-sheet movements during embryogenesis.

  • MLKs are implicated in the control of neuronal apoptosis, and are potential targets for inhibition in many neurogenerative diseases including Huntington's.

Abstract

Mixed-lineage kinases (MLKs) are serine/threonine protein kinases that regulate signalling by the c-Jun amino-terminal kinase (JNK) and p38 mitogen-activated-protein kinase (MAPK) pathways. MLKs are represented in the genomes of both Caenorhabditis elegans and Drosophila melanogaster. The Drosophila MLK Slipper regulates JNK to control dorsal closure during embryonic morphogenesis. In mammalian cells, MLKs are implicated in the control of apoptosis and are potential drug targets for many neurodegenerative diseases.

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Figure 1: Mixed-lineage kinases.
Figure 2: Comparison of the MLK family — conserved domains and phylogenetic history.
Figure 3: SH3-mediated autoinhibition of MLKs.
Figure 4: Fly dorsal closure.
Figure 5: Possible MLK2–huntingtin interaction.

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Authors and Affiliations

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DATABASES

LocusLink

ApoER2

APP

ASK1

ATF2

Bcl-2

Bmp4

Cdc42

DLK

eEF2K

ERK5

FHF1

GluR6

huntingtin

IB1

IB2

IL-2

IL-4

JIP1

JIP2

JIP3

JNK1

JNK3

Jun

LRP-1

LZK

MEF2

Megalin

MEKK1

MEKK4

MKK4

MKK7

MLK1

MLK2

MLK3

Mos

MSK

p38α

p38δ

Raf-1

RasGRF1

RhoGEF

TAK1

TC10

Tiam1

TNFα

Tpl

Vav

ZAK

Flybase

Bsk

dJun

Dpp

dRac

dTAK

Hep

kayak

Msn

Slipper

Sunday driver

ProSite

CRIB

SAM

SH3

Glossary

PHOSPHORELAYS

Complex pathways in which phosphoryl groups are transferred through several signal-transduction proteins before reaching the target protein.

CYCLOHEXIMIDE

Antibiotic produced by some Streptomyces sp. that interferes with protein synthesis in eukaryotes by inhibiting peptidyltransferase activity of the 60S ribosomal subunit.

ACTIVATOR-PROTEIN 1 (AP-1) TRANSCRIPTION-FACTOR COMPLEX

A transcription-factor complex that comprises a dimer of members of the Fos and Jun families of nuclear phosphoproteins.

SRC-HOMOLOGY-3 (SH3) DOMAIN

Protein sequence of 50 amino acids that recognizes and binds sequences rich in proline.

CRIB MOTIF

A 14–16-amino-acid sequence with eight conserved residues that is essential for the binding of signalling molecules to GTP-bound forms of Rac and Cdc42.

LEUCINE ZIPPER

A leucine-rich domain within a protein that binds to other proteins with a similar domain.

RHO-FAMILY GTPASES

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

COILED-COIL

A protein domain that forms a bundle of two or three α-helices. Short coiled-coil domains are involved in protein interactions but long coiled-coil domains, which form long rods, occur in structural or motor proteins.

ACTIVATION LOOP

A conserved structural motif in kinase domains that needs to be phosphorylated for full activation of most kinases.

PRENYLATION

The enzymatic addition of prenyl moieties (geranyl, farnesyl or geranylgeranyl groups) to a protein as a post-translational modification.

YEAST TWO-HYBRID SCREEN

A technique used to test whether two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

GUANINE-NUCLEOTIDE-EXCHANGE FACTOR

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

SCAFFOLDING PROTEIN

A protein that has specific binding sites and is therefore important in the assembly, structure and function of larger molecular complexes.

KINESIN

Microtubule-based molecular motor, most often directed towards the plus end of microtubules.

DORSAL ECTODERM

The outer of the three embryonic germ layers; this gives rise to the entire central nervous system.

XENOGRAFT

Tissue or organ graft between species. These grafts are usually rejected.

NUDE MICE

A mutation in mice that causes both hairlessness and defective formation of the thymus, which results in a lack of mature T cells.

JURKAT T-LYMPHOMA CELLS

Human leukaemic T-cell line used to study several aspects of T-cell biology and signalling, especially signal-transduction events initiated by the T-cell receptor.

DOMINANT-NEGATIVE

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

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Gallo, K., Johnson, G. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3, 663–672 (2002). https://doi.org/10.1038/nrm906

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