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hSiah2 is a new Vav binding protein which inhibits Vav-mediated signaling pathways
A Germani1, F Romero, M Houlard
1Institut Cochin de Génétique Moléculaire, U363 INSERM, Hôpital Cochin, Université Paris V, 75014 Paris, France. germani@cochin.inserm.fr
Abstract:
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.
Insights
The proto-oncogene Vav interacts with hSiah2, a protein involved in cell development. hSiah2 negatively regulates Vav
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- The proto-oncogene Vav is a Rac1-GDP/GTP exchanger protein crucial for cytoskeletal organization and signaling pathways, including stress-activated protein kinases (SAPK/JNKs).
- Vav overexpression potentiates both basal and T-cell receptor (TCR)-mediated activation of nuclear factor of activated T cells (NFAT).
Purpose of the Study:
- To investigate the interaction between the proto-oncogene Vav and hSiah2, a mammalian homolog of Drosophila Seven in absentia (Sina).
- To elucidate the functional consequences of this interaction on Vav-mediated signaling pathways.
Main Methods:
- In vitro and in vivo interaction studies between Vav and hSiah2.
- Co-localization studies in hematopoietic cells.
- Analysis of the domains required for Vav-hSiah2 interaction.
- Assessment of hSiah2's effect on Vav-induced NFAT-dependent transcription and JNK activation.
Main Results:
- Vav and hSiah2 interact physically in vitro and in vivo, localizing to the cytoplasm of hematopoietic cells.
- The Src homology domain of Vav and the C-terminal region of hSiah2 are essential for their interaction.
- hSiah2 negatively regulates Vav-induced basal and TCR-mediated NFAT-dependent transcription.
- Overexpression of hSiah2 inhibits oncogenic Vav-induced JNK activation, independent of proteasome degradation.
Conclusions:
- hSiah2 acts as a negative regulator of Vav signaling, impacting NFAT transcription and JNK activation.
- The interaction between Vav and hSiah2 provides a novel regulatory mechanism in hematopoietic cell signaling.
- Understanding this interaction may offer new therapeutic targets in oncology.