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The Cause of ErbB2 Receptor Resistance to Downregulation

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Abstract

ErbB2/HER2 is a tyrosine kinase receptor belonging to the family of epidermal growth factor receptors (EGFRs); it is overexpressed in 25–30% of human breast cancer cases and has a number of structural and functional differences from other receptors of this family. Typically, the activation of tyrosine kinase receptors, i.e., formation of their homo- or heterodimers, and the subsequent signal transmission into the cell occurs when the ligand is bound to them. After dimers are formed, the internalization of a complex takes place, which plays a key role in the regulation of receptor activity. Unlike other receptors of the family, ErbB2 does not have natural ligands, but is the preferred partner for the formation of heterodimers with other members of the ErbB family. ErbB2 is also resistant to internalization and degradation. Thus, staying for a long time at the cell membrane after activation, ErbB2 continues to transmit regulatory signals to the cell nucleus. Although mechanisms ensuring the ErbB2 resistance to downregulation are not fully understood, a significant pool of experimental data suggests that such key points as interaction with Hsp90 chaperon, the ability to suppress the formation of clathrin pits, the ability to quickly return to the membrane from early endosomes, and interaction with the calcium pump PMCA2, allow ErbB2 receptor to avoid internalization.

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Abbreviations

АТP:

adenosine triphosphate

CLASPs:

clathrin-associated sorting peptides

EGFR:

epidermal growth factor receptor

ErbB:

viral oncogene B of erythroblastic bird leukemia

HER2:

human epidermal growth factor receptor 2

Hsp90:

heat shock protein 90

PMCA2:

plasma membrane calcium ATPase-2

scFv:

single-chain variable fragment

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Authors and Affiliations

  1. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia

    E. I. Shramova, G. M. Proshkina & S. M. Deyev

  2. Moscow State University, Moscow, Russia

    S. M. Deyev

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  1. E. I. Shramova
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  2. G. M. Proshkina
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  3. S. M. Deyev
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Original Russian Text © E.I. Shramova, G.M. Proshkina, S.M. Deyev, 2018, published in Bioorganicheskaya Khimiya, 2018, Vol. 44, No. 3, pp. 267–277.

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Shramova, E.I., Proshkina, G.M. & Deyev, S.M. The Cause of ErbB2 Receptor Resistance to Downregulation. Russ J Bioorg Chem 44, 279–288 (2018). https://doi.org/10.1134/S1068162018030147

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