Adaptor protein APS binds the NH2-terminal autoinhibitory domain of guanine nucleotide exchange factor Vav3 and augments its activity.
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.
Yabana
Naoyuki
N
Division of Genetics, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1 Minato, Tokyo, Japan.
Shibuya
Masabumi
M
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001798:Blood Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C000715470:MAS1 protein, human; D010750:Phosphoproteins; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins; C107249:SH2B2 protein, human; C488161:Sh2b2 protein, mouse; C402726:Sh2d2a protein, mouse; C496621:VAV3 protein, human; C496622:Vav3 protein, mouse; C039077:platelet protein P47; D014443:Tyrosine