Pari passu dimers of dimers

Sliwkowski, Mark X.

doi:10.1073/pnas.1209959109

Cited by 3 publications

(2 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the steric hindrance between domains I and III of HER2, 'cetuximab-like' anti-HER2 antibodies cannot bind to the area on HER2 as that of cetuximab on EGFR, and F0178C1 may have attained the best relative binding position. Although Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy, recently, more and more data point out that trastuzumab does not block ErbB2 activation but rather disrupts noncanonical ErbB2-ErbB3 interactions that result in constitutive ErbB3 activation, 13,35 in this study, we mainly focused on the HRGdependent ErbB2 activation, and the impact of F0178-C1 on the whole ErbB2 signaling network is ongoing.…”

Section: Discussionmentioning

confidence: 99%

Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies

Wang

Zhang

et al. 2014

mAbs

View full text Add to dashboard Cite

HER2, a ligand-free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti-HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer; however, resistance to trastuzumab is common. The development of monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of ErbB2 signaling, especially HER2/HER3 signaling. Use of such antibodies may have clinical benefits if these antibodies can become widely accepted. Here, we describe a novel anti-HER2 antibody, hHERmAb-F0178C1, which was isolated from a screen of a phage display library. A step-by-step optimization method was employed to maximize the inhibitory effect of this anti-HER2 antibody. Crystallographic analysis was used to determine the three-dimensional structure to 3.5 Å resolution, confirming that the epitope of this antibody is in domain III of HER2. Moreover, this novel anti-HER2 antibody exhibits superior efficacy in blocking HER2/HER3 heterodimerization and signaling, and its use in combination with pertuzumab has a synergistic effect. Characterization of this antibody revealed the important role of a ligand binding site within domain III of HER2. The results of this study clearly indicate the unique potential of hHERmAb-F0178C1, and its complementary inhibition effect on HER2/HER3 signaling warrants its consideration as a promising clinical treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies

Wang

Zhang

et al. 2014

mAbs

View full text Add to dashboard Cite

show abstract

“…Thus, while HER3 must in an EGFR/HER3 or HER2/HER3 heterodimer be phosphorylated primarily in trans [41] , its partner EGFR or HER2 might still be phosphorylated in cis in such heterodimers, adding to the diversity of their downstream signaling. It should be noted that although HER2 is known to be phosphorylated in the context of HER2/HER3 heterodimers, this has also been attributed to the formation of higher-order receptor oligomers [42] , [43] .…”

Section: Discussionmentioning

confidence: 99%

Coarse-Grained Molecular Simulation of Epidermal Growth Factor Receptor Protein Tyrosine Kinase Multi-Site Self-Phosphorylation

Koland

2014

PLoS Comput Biol

View full text Add to dashboard Cite

Upon the ligand-dependent dimerization of the epidermal growth factor receptor (EGFR), the intrinsic protein tyrosine kinase (PTK) activity of one receptor monomer is activated, and the dimeric receptor undergoes self-phosphorylation at any of eight candidate phosphorylation sites (P-sites) in either of the two C-terminal (CT) domains. While the structures of the extracellular ligand binding and intracellular PTK domains are known, that of the ∼225-amino acid CT domain is not, presumably because it is disordered. Receptor phosphorylation on CT domain P-sites is critical in signaling because of the binding of specific signaling effector molecules to individual phosphorylated P-sites. To investigate how the combination of conventional substrate recognition and the unique topological factors involved in the CT domain self-phosphorylation reaction lead to selectivity in P-site phosphorylation, we performed coarse-grained molecular simulations of the P-site/catalytic site binding reactions that precede EGFR self-phosphorylation events. Our results indicate that self-phosphorylation of the dimeric EGFR, although generally believed to occur in trans, may well occur with a similar efficiency in cis, with the P-sites of both receptor monomers being phosphorylated to a similar extent. An exception was the case of the most kinase-proximal P-site-992, the catalytic site binding of which occurred exclusively in cis via an intramolecular reaction. We discovered that the in cis interaction of P-site-992 with the catalytic site was facilitated by a cleft between the N-terminal and C-terminal lobes of the PTK domain that allows the short CT domain sequence tethering P-site-992 to the PTK core to reach the catalytic site. Our work provides several new mechanistic insights into the EGFR self-phosphorylation reaction, and demonstrates the potential of coarse-grained molecular simulation approaches for investigating the complexities of self-phosphorylation in molecules such as EGFR (HER/ErbB) family receptors and growth factor receptor PTKs in general.

show abstract

EGF receptor family: twisting targets for improved cancer therapies

et al. 2014

View full text Add to dashboard Cite

The epidermal growth factor receptor (EGFR) undergoes a conformational change in response to ligand binding. The ligand-induced changes in cell surface aggregation and mobility have a profound effect on the function of all the family members. Ligand also activates the EGFR intracellular kinase, stimulating proliferation and cell survival. The EGFR family are often activated, overexpressed or mutated in cancer cells and therapeutic drugs (including antibodies) can slow the progress of some cancers. This article provides a brief, annotated summary of the presentations and discussion which occurred at the Epidermal Growth Factor Receptor - Future Directions Conference held in Jerusalem in November 2013.

show abstract

Pari passu dimers of dimers

Cited by 3 publications

References 16 publications

Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies

Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies

Coarse-Grained Molecular Simulation of Epidermal Growth Factor Receptor Protein Tyrosine Kinase Multi-Site Self-Phosphorylation

EGF receptor family: twisting targets for improved cancer therapies

Contact Info

Product

Resources

About