The juxtamembrane region of the EGF receptor functions as an activation domain.

@article{Brewer2009TheJR,
  title={The juxtamembrane region of the EGF receptor functions as an activation domain.},
  author={Monica Red Brewer and Sung Hee Choi and Diego Alvarado and K. Moravcevic and A. Pozzi and M. Lemmon and G. Carpenter},
  journal={Molecular cell},
  year={2009},
  volume={34 6},
  pages={
          641-51
        }
}
In several growth factor receptors, the intracellular juxtamembrane (JM) region participates in autoinhibitory interactions that must be disrupted for tyrosine kinase activation. Using alanine scanning mutagenesis and crystallographic approaches, we define a domain within the JM region of the epidermal growth factor receptor (EGFR) that instead plays an activating--rather than autoinhibitory--role. Mutations in the C-terminal 19 residues of the EGFR JM region abolish EGFR activation. In a… Expand
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment
TLDR
It is shown that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. Expand
Molecular basis for multimerization in the activation of the epidermal growth factor receptor
TLDR
A structural model for EGFR multimerization through self-association of ligand-bound dimers is proposed, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation. Expand
Consequences of replacing EGFR juxtamembrane domain with an unstructured sequence
TLDR
The results suggest that the JM domain does not stabilize the inactive EGFR dimer in the absence of ligand, and is likely critical only for the last step of EGFR activation, the ligand-induced transition from the inactive to active dimer. Expand
The regulatory role of the juxtamembrane region in the activity of the epidermal growth factor receptor
TLDR
The role of the JXM (juxtamembrane) domain in EGFR structure and activity has only recently begun to be elucidated through biochemical, biophysical and structural studies. Expand
The regulatory role of the juxtamembrane region in the activity of the epidermal growth factor receptor.
  • A. Boran
  • Biology, Medicine
  • Biochemical Society transactions
  • 2012
TLDR
The role of the JXM (juxtamembrane) domain in EGFR structure and activity has only recently begun to be elucidated through biochemical, biophysical and structural studies. Expand
Studies of the Allosteric Activation of the Epidermal Growth Factor Receptor
Author(s): Engel, Katherine Anne | Advisor(s): Kuriyan, John | Abstract: Ligand binding to the extracellular domain of the epidermal growth factor receptor (EGFR) results in receptor dimerization andExpand
Conformational regulation of the EGFR kinase core by the juxtamembrane and C‐terminal tail: A molecular dynamics study
TLDR
This study performs unrestrained and targeted molecular dynamics simulations on the active and inactive states of EGFR, followed by principal component analysis on the simulated trajectories, to identify correlated motions in the EGFR kinase domain upon dimerization, and pinpoints key residues involved in this conformational coupling. Expand
A structural perspective on the regulation of the epidermal growth factor receptor.
TLDR
The epidermal growth factor receptor is a receptor tyrosine kinase that plays a critical role in the pathogenesis of many cancers, and its activation mechanism is reviewed here. Expand
Autophosphorylation of EGFR at Y954 facilitated homodimerization and enhanced downstream Ca2+ / ERK signals.
TLDR
The previously anonymous role of phosphorylation at the latch interface of kinase domains in regulating EGFR dimerization is delineated and identified that threonineosphorylation in the latch domain negatively regulated EGFRdimerization and the downstream signals. Expand
Mutations in the Polybasic Juxtamembrane Sequence of Both Plasma Membrane- and Endoplasmic Reticulum-localized Epidermal Growth Factor Receptors Confer Ligand-independent Cell Transformation*
TLDR
It is found that charge-silencing mutagenesis within this juxtamembrane region of the epidermal growth factor receptor (EGFR) results in the generation of a mutant receptor that spontaneously transforms NIH 3T3 cells in a ligand-independent manner. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 58 REFERENCES
Epidermal growth factor receptor juxtamembrane region regulates allosteric tyrosine kinase activation
TLDR
An integral role is revealed for the intracellular JM region of ErbB-1 in allosteric kinase activation. Expand
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment
TLDR
It is shown that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. Expand
A basic peptide within the juxtamembrane region is required for EGF receptor dimerization.
TLDR
It is shown that P13 is required for proper dimerization of the receptor, and a novel role for the juxtamembrane domain (JM) of EGFR in mediating intracellularDimerization and thus receptor kinase activation and function is suggested. Expand
Autoinhibition of the Kit Receptor Tyrosine Kinase by the Cytosolic Juxtamembrane Region
TLDR
Results show the Kit kinase is autoinhibited through an intramolecular interaction with the juxtamembrane domain, and tyrosine phosphorylation and oncogenic mutations relieved the regulatory function of the juXTamem brane domain. Expand
An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor
TLDR
It is found that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine in the activation loop, which suggests that the Kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Expand
Structural Basis for Autoinhibition of the EphB2 Receptor Tyrosine Kinase by the Unphosphorylated Juxtamembrane Region
TLDR
It is proposed that the autoinhibitory mechanism employed by EphB2 is a more general device through which receptor tyrosine kinases are controlled. Expand
Mutation of Di-leucine residues in the juxtamembrane region alters EGF receptor expression.
TLDR
It is demonstrated that removal of either of the di-leucines leads to generation of inactivating carboxy-truncated receptors, suggesting that the two di-Leucine motifs within the juxtamembrane region of the EGFR are important for ensuring normal receptor expression. Expand
The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.
TLDR
The crystal structure of the autoinhibited form of FLT3 is determined and the detailed inhibitory mechanism of the JM domain is revealed, which is likely utilized by other members of type III receptor tyrosine kinases. Expand
Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor*
TLDR
It is found that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor, which is distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Expand
An Electrostatic Engine Model for Autoinhibition and Activation of the Epidermal Growth Factor Receptor (EGFR/ErbB) Family
We propose a new mechanism to explain autoinhibition of the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases based on a structural model that postulates both theirExpand
...
1
2
3
4
5
...