Abstract:
:Overexpression of the receptor tyrosine kinase (RTK) erbB2 (also designated neu or HER2) was implicated in causing a variety of human cancers, including mammary and ovarian carcinomas. Ligand-induced receptor dimerization is critical for stimulation of the intrinsic protein tyrosine kinase (PTK) of RTKs. It was therefore proposed that PTK activity is stimulated as a result of the reorientation of the cytoplasmic domains within receptor dimers, leading to transautophosphorylation and stimulation of enzymatic activity. Here, we propose a molecular mechanism for rotation-coupled activation of the erbB2 receptor. Using a computational exploration of conformation space of the transmembrane (TM) segments of an erbB2 homodimer, we found two stable conformations of the TM domain. We suggest that these conformations correspond to the active and inactive states of erbB2, and that the receptor molecules may switch from one conformation to the other without crossing exceedingly unfavorable states. This model provides an explanation for the biochemical and oncogenic properties of erbB2, such as the effects of erbB2 overexpression on kinase activity and cell transformation. Furthermore, the opposing effects of the neu* activating oncogenic point mutation and the Val-655-->Ile single-nucleotide polymorphism shown to be linked to reduced risk of breast cancer are explained in terms of shifts in the equilibrium between the active and inactive states of erbB2 in vivo.
journal_name
Proc Natl Acad Sci U S Aauthors
Fleishman SJ,Schlessinger J,Ben-Tal Ndoi
10.1073/pnas.252640799keywords:
subject
Has Abstractpub_date
2002-12-10 00:00:00pages
15937-40issue
25eissn
0027-8424issn
1091-6490pii
252640799journal_volume
99pub_type
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