NDLI: A putative molecular-activation switch in the transmembrane domain of erbB2

Content Provider	PubMed Central
Author	Fleishman, Sarel J. Schlessinger, Joseph Nir, Ben-tal
Copyright Year	2002
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.
Related Links	http://dx.doi.org/10.1073/pnas.252640799
Ending Page	15940
Page Count	4
Starting Page	15937
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	99
Language	English
Publisher	National Academy of Sciences
Publisher Date	2002-12-10
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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