hSiah2 is a new Vav binding protein which inhibits Vav-mediated signaling pathways.
The hematopoietic proto-oncogene vav has been characterized as a Rac1-GDP/GTP exchanger protein which regulates cytoskeletal reorganization as well as signaling pathways leading to the activation of stress-activated protein kinases (SAPK/JNKs). Furthermore, vav overexpression enhances basal and T-cell receptor (TCR)-mediated stimulation of the nuclear factor of activated T cells (NFAT). We report here the interaction between Vav and hSiah2, a mammalian homolog of Drosophila Seven in absentia (Sina) that has been implicated in R7 photoreceptor cell formation during Drosophila eye development via the proteasome degradation pathway. Vav and hSiah2 interact in vitro and in vivo and colocalize in the cytoplasm of hematopoietic cells. The Src homology domain of Vav and the C-terminal region of hSiah2 are required for this interaction. We provide evidence for a negative regulation by hSiah2 of Vav-induced basal and TCR-mediated NFAT-dependent transcription. Overexpression of hSiah2 also inhibits the onco-Vav-induced JNK activation. Although the Vav-interacting domain is located in the C-terminal portion of hSiah2, the N-terminal region of hSiah2 is necessary for the inhibitory role that seems to be independent of the proteasome degradation.
Germani
A
A
Institut Cochin de Génétique Moléculaire, U363 INSERM, Hôpital Cochin, Université Paris V, 75014 Paris, France. germani@cochin.inserm.fr
Romero
F
F
Houlard
M
M
Camonis
J
J
Gisselbrecht
S
S
Fischer
S
S
Varin-Blank
N
N
D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C496618:VAV1 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases