Abstract
Suppressor of cytokine signaling 3 (SOCS3) is involved in Bcr-Abl-induced tumorigenesis. However, how SOCS3 interacts with Bcr-Abl and is regulated by Abl kinases remains largely unknown. Since c-Abl plays a critical role in tumorigenesis, we asked whether SOCS3 is regulated by c-Abl-dependent phosphorylation. Here, we found that SOCS3 interacted with all three Abl kinases (Bcr-Abl, v-Abl, and c-Abl), and SH1 domain of the Abl kinases was critically required for such interaction. Furthermore, the SH2 domain of SOCS3 was sufficient to pull down the SH1 domain but not the full length of Bcr-Abl. Importantly, SOCS3 was highly tyrosine phosphorylated by c-Abl, leading to impairment of its ability to suppress JAK8+72 activity. In addition, disrupting the tyrosine phosphorylation of SOCS3 promoted apoptosis of c-Abl-expressing cells and impeded xenograft growth of these tumor cells in nude mice. The results demonstrate that SOCS3 is highly tyrosine phosphorylated by c-Abl and that tyrosine phosphorylation of SOCS3 is required for the survival and tumorigenesis of certain cells. Our findings provide novel insights into complicated mechanisms underlying the oncogenic function of Abl kinases.