Abstract
The N-terminal calponin homology (CH) domain of Vav guanine nucleotide exchange factor is thought to serve a regulatory role in the autoinhibition, however, its precise function is not entirely clear. We found that the adaptor molecule APS could bind the CH domain of Vav3, a member of the vav proto-oncogene family. The binding of Vav3 and APS was apparently stabilized by the tyrosine phosphorylation of Vav3 by Lck, and the association of APS with Vav3 in turn enhanced the Lck-mediated phosphorylation of Vav3. Focus formation assays demonstrated that APS could increase the transforming activity of proto-Vav3. Further analyses revealed that the Vav3 CH domain could bind the pleckstrin homology (PH) domain of APS and that this binding was indispensable to enhance the transforming activity of Vav3. We present here a novel stimulatory mechanism of Vav3 in which APS directly relieves the autoinhibitory CH domain and furthermore enhances its tyrosine phosphorylation by Lck.
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Acknowledgements
We thank Drs Tohru Tezuka and Tadashi Yamamoto for their gift of expression plasmid encoding Lck, Dr Takaya Satoh for the expression plasmid of proto-Dbl. This work was supported by Grants-in-Aid for Special Project Research on Cancer-Bioscience 12215024 from the Ministry of Education, Culture, Sports, Science, and Technology in Japan and for the program ‘Research for the Future’ of Japan Society for Promotion of Science
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Yabana, N., Shibuya, M. Adaptor protein APS binds the NH2-terminal autoinhibitory domain of guanine nucleotide exchange factor Vav3 and augments its activity. Oncogene 21, 7720–7729 (2002). https://doi.org/10.1038/sj.onc.1205927
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DOI: https://doi.org/10.1038/sj.onc.1205927
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