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Juxtamembrane autoinhibition in receptor tyrosine kinases

Nature Reviews Molecular Cell Biology volume 5, pages 464–471 (2004)Cite this article

Key Points

  • Receptor tyrosine kinases (RTKs) are transmembrane receptors that have intrinsic, cytoplasmic tyrosine kinase activity. These receptors are activated by ligand binding, which stabilizes a dimeric receptor configuration and facilitates trans phosphorylation of tyrosine (Tyr) residues in the cytoplasmic domain.

  • In addition to generating docking sites for downstream signalling proteins, Tyr phosphorylation stimulates receptor catalytic (tyrosine kinase) activity. For most RTKs, Tyr phosphorylation in the activation segment of the kinase domain is stimulatory for activity. And, for a subset of RTKs, Tyr phosphorylation in the juxtamembrane region of the receptor (between the transmembrane helix and the kinase domain) is also stimulatory.

  • Juxtamembrane autoinhibition, which is relieved by Tyr phosphorylation, has been shown biochemically to occur in Eph receptors (the receptors for ephrins), the platelet-derived growth factor (PDGF) receptor family, and in muscle-specific kinase (MUSK).

  • For Eph receptors and PDGF receptor family members, structural studies have revealed the mechanisms by which the unphosphorylated juxtamembrane region inhibits catalytic activity. In both cases, interactions between residues in the juxtamembrane region and the kinase domain prevent the kinase from adopting an active state, although the detailed mechanisms are distinct.

  • Point mutations and short in-frame deletions in the juxtamembrane regions of KIT (a PDGF receptor family member) and PDGF receptor-α that cause gastrointestinal stromal tumours disrupt the interactions between the juxtamembrane region and the kinase domain, which renders the receptors constitutively active.

  • Our ability to design small-molecule kinase inhibitors and activators should improve as a result of an increased structural understanding of juxtamembrane autoinhibition.

Abstract

Receptor tyrosine kinases are essential mediators of cell growth, differentiation, migration and metabolism. Accordingly, their catalytic activity is tightly regulated by several mechanisms including autoinhibition. Recent structural studies, together with biochemical experiments, are now unravelling the molecular mechanisms by which the juxtamembrane region (between the transmembrane helix and the cytoplasmic kinase domain) negatively regulates catalytic activity in various receptor tyrosine kinases.

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Figure 1: A general autoinhibition/activation model for receptor tyrosine kinases.
Figure 2: Juxtamembrane sequences of selected receptor tyrosine kinases.
Figure 3: Juxtamembrane autoinhibitory mechanisms in receptor tyrosine kinases.

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Acknowledgements

I acknowledge research support from the National Institutes of Health and the American Diabetes Association.

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Authors and Affiliations

  1. Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, 10016, USA

    Stevan R. Hubbard

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DATABASES

Protein Data Bank

EGF receptor kinase domain

EPHB2 cytoplasmic domain

FGFR1 kinase domain

FLT3 crystal structure

KIT cytoplasmic domain

phosphorylated insulin receptor tyrosine kinase domain

TIE2 kinase domain

unphosphorylated insulin receptor tyrosine kinase domain

unphosphorylated MUSK cytoplasmic domain

VEGFR2 kinase domain

Swiss-Prot

CSF1R

EPHA4

EPHB2

FGFR1

FGFR3

FKBP12

FLT3

IGF1R

IRS1

KIT

MUSK

PDGFRα

PDGFRβ

TIE2

VEGFR2

FURTHER INFORMATION

Stevan R. Hubbard's laboratory

Glossary

PROTEIN TYROSINE KINASE

An enzyme that transfers the γ-phosphate of ATP to tyrosine residues in protein substrates.

RECEPTOR TYROSINE KINASE

(RTK). A cell-surface receptor that has an intracellular protein tyrosine kinase domain.

TRANS PHOSPHORYLATION

The transfer of a phosphate group by a protein kinase to a residue in a different kinase molecule.

CIS PHOSPHORYLATION

The transfer of a phosphate group by a protein kinase to a residue in the same kinase molecule.

SRC HOMOLOGY-2 DOMAIN

(SH2 domain). An ∼100-residue domain that binds to phosphorylated tyrosine sequences in proteins.

ACTIVATION SEGMENT/LOOP

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

BASAL-LEVEL ACTIVITY

The catalytic activity of a protein kinase that has not been activated, for example, by ligand-mediated phosphorylation.

AUTOINHIBITION

The suppression of protein activity owing to interactions within the protein.

JUXTAMEMBRANE REGION

The polypeptide segment in a receptor that connects the transmembrane helix to the kinase domain.

AUTOPHOSPHORYLATION

The transfer of a phosphate group by a protein kinase either to a residue in the same kinase molecule (cis) or to a residue in a different kinase molecule (trans) but of the same type.

DISORDERED

In a crystal structure, this describes a polypeptide segment that does not adopt a preferred conformation, but rather multiple conformations.

PROTEIN SERINE/THREONINE KINASE

An enzyme that transfers the γ-phosphate of ATP to serine or threonine residues in protein substrates.

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Hubbard, S. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol 5, 464–471 (2004). https://doi.org/10.1038/nrm1399

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