Unliganded EphA3 dimerization promoted by the SAM domain

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Abstract

Erythropoietin-producing hepatocellular carcinoma A3 (EphA3) can form dimers in the absence of ligand binding, which are stabilized by the sterile α-motif (SAM) domain. This challenges the current understanding of EphA3 activation events and establishes a new role for the EphA3 SAM domain in receptor-receptor interactions.

Abstract

The erythropoietin-producing hepatocellular carcinoma A3 (EphA3) receptor tyrosine kinase (RTK) regulates morphogenesis during development and is overexpressed and mutated in a variety of cancers. EphA3 activation is believed to follow a ‘seeding mechanism’ model, in which ligand binding to the monomeric receptor acts as a trigger for signal-productive receptor clustering. We study EphA3 lateral interactions on the surface of live cells and we demonstrate that EphA3 forms dimers in the absence of ligand binding. We further show that these dimers are stabilized by interactions involving the EphA3 sterile α-motif (SAM) domain. The discovery of unliganded EphA3 dimers challenges the current understanding of the chain of EphA3 activation events and suggests that EphA3 may follow the ‘pre-formed dimer’ model of activation known to be relevant for other receptor tyrosine kinases. The present work also establishes a new role for the SAM domain in promoting Eph receptor lateral interactions and signalling on the cell surface.

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The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.

Jeffrey Ross, Elzbieta A Slodkowska, W Symmans … (2009)

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.

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Cells respond to mechanical stress by rapid disassembly of caveolae.

Bidisha Sinha, Darius Köster, Richard Ruez … (2011)

The functions of caveolae, the characteristic plasma membrane invaginations, remain debated. Their abundance in cells experiencing mechanical stress led us to investigate their role in membrane-mediated mechanical response. Acute mechanical stress induced by osmotic swelling or by uniaxial stretching results in a rapid disappearance of caveolae, in a reduced caveolin/Cavin1 interaction, and in an increase of free caveolins at the plasma membrane. Tether-pulling force measurements in cells and in plasma membrane spheres demonstrate that caveola flattening and disassembly is the primary actin- and ATP-independent cell response that buffers membrane tension surges during mechanical stress. Conversely, stress release leads to complete caveola reassembly in an actin- and ATP-dependent process. The absence of a functional caveola reservoir in myotubes from muscular dystrophic patients enhanced membrane fragility under mechanical stress. Our findings support a new role for caveolae as a physiological membrane reservoir that quickly accommodates sudden and acute mechanical stresses. Copyright © 2011 Elsevier Inc. All rights reserved.

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Spatial control of EGF receptor activation by reversible dimerization on living cells.

Inhee Chung, Robert Akita, Richard Vandlen … (2010)

Epidermal growth factor receptor (EGFR) is a type I receptor tyrosine kinase, the deregulation of which has been implicated in a variety of human carcinomas. EGFR signalling is preceded by receptor dimerization, typically thought to result from a ligand-induced conformational change in the ectodomain that exposes a loop (dimerization arm) required for receptor association. Ligand binding may also trigger allosteric changes in the cytoplasmic domain of the receptor that is crucial for signalling. Despite these insights, ensemble-averaging approaches have not determined the precise mechanism of receptor activation in situ. Using quantum-dot-based optical tracking of single molecules combined with a novel time-dependent diffusivity analysis, here we present the dimerization dynamics of individual EGFRs on living cells. Before ligand addition, EGFRs spontaneously formed finite-lifetime dimers kinetically stabilized by their dimerization arms. The dimers were primed both for ligand binding and for signalling, such that after EGF addition they rapidly showed a very slow diffusivity state that correlated with activation. Although the kinetic stability of unliganded dimers was in principle sufficient for EGF-independent activation, ligand binding was still required for signalling. Interestingly, dimers were enriched in the cell periphery in an actin- and receptor-expression-dependent fashion, resulting in a peripheral enhancement of EGF-induced signalling that may enable polarized responses to growth factors.

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Author and article information

Journal

Journal ID (nlm-ta): Biochem J

Journal ID (iso-abbrev): Biochem. J

Journal ID (hwp): ppbiochemj

Journal ID (publisher-id): BJ

Title: Biochemical Journal

Publisher: Portland Press Ltd.

ISSN (Print): 0264-6021

ISSN (Electronic): 1470-8728

Publication date (Electronic preprint): 31 July 2015

Publication date (Electronic): 21 September 2015

Publication date (Print): 1 October 2015

Volume: 471

Issue: Pt 1 ( displayID: 1 )

Pages: 101-109

Affiliations

[* ]Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, U.S.A.

[† ]Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21212, U.S.A.

[‡ ]Vaccine Center, The Wistar Institute, Philadelphia, PA 19104, U.S.A.

[§ ]Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, U.S.A.

Author notes

[1]

These authors contributed equally to this work.

[ ² ]To whom correspondence should be addressed (email kh@ 123456jhu.edu ).

Article

Publisher ID: BJ20150433

DOI: 10.1042/BJ20150433

PMC ID: 4692061

PubMed ID: 26232493

SO-VID: 873ed90c-8d07-4876-8d17-566b134631a3

History

Date received : 7 April 2015

Date revision received : 28 July 2015

Date accepted : 31 July 2015

Page count

Figures: 6, Tables: 1, Equations: 6, References: 76, Pages: 9

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