Suppressor of cytokine signaling-1 inhibits VAV function through protein degradation.

Suppressor of cytokine signaling-1 (SOCS1) is an inducible Src homology 2 (SH2)-containing protein that negatively regulates cytokine and growth factor signaling required during thymic development. Recent evidence indicates that SOCS1 interacts with elongins B and C, which are components of a ubiquitin ligase complex, VCB (VHL/elonginC/B), based on the VHL (von Hippel Lindau) tumor suppressor protein. SOCS1 has previously been shown to operate as an inhibitor of Janus kinases. Here we show that SOCS1 has the distinct function of targeting the hematopoietic specific guanine nucleotide exchange factor, VAV, for ubiquitin-mediated protein degradation. VAV and SOCS1 form a protein complex through interactions between the VAV NH(2)-terminal regulatory region and the SH2 domain of SOCS1 in a phosphotyrosine-independent manner. SOCS1 decreases the steady state levels of cotransfected VAV and onco-VAV and reduces the focus forming activity of onco-VAV. SOCS1 stimulates the polyubiquitination of VAV proteins in vivo, which was stabilized by proteasomal inhibitors. These results suggest that SOCS1 programs VAV degradation by acting as a substrate-specific recognition component of a VCB-like ubiquitin ligase complex.