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Interaction of Abl Tyrosine Kinases with SOCS3 Impairs Its Suppressor Function in Tumorigenesis
Riyue Feng1, Xuefei Wang2, Jianning Li2
1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China; Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
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.
Insights
Suppressor of cytokine signaling 3 (SOCS3) is tyrosine phosphorylated by c-Abl, impairing its tumor-suppressive function. This phosphorylation is crucial for cancer cell survival and growth, revealing new insights into Abl kinase oncogenic mechanisms.
Area of Science:
- Oncogenesis
- Signal Transduction
- Molecular Biology
Background:
- Suppressor of cytokine signaling 3 (SOCS3) plays a role in Bcr-Abl-induced tumorigenesis.
- The precise interaction and regulation mechanisms between SOCS3 and Abl kinases are not fully understood.
- c-Abl kinase is a critical factor in tumorigenesis.
Purpose of the Study:
- To investigate whether SOCS3 is regulated by c-Abl-dependent phosphorylation.
- To elucidate the interaction between SOCS3 and Abl kinases.
Main Methods:
- Co-immunoprecipitation assays to study protein interactions.
- Tyrosine phosphorylation assays.
- In vitro kinase assays.
- Cell apoptosis assays.
- Xenograft tumor growth studies in nude mice.
Main Results:
- SOCS3 interacts with Bcr-Abl, v-Abl, and c-Abl kinases via the Abl kinase SH1 domain.
- SOCS3 is tyrosine phosphorylated by c-Abl, which impairs its ability to suppress JAK8+72 activity.
- Disruption of SOCS3 tyrosine phosphorylation promotes apoptosis in c-Abl-expressing cells and inhibits tumor growth in vivo.
Conclusions:
- SOCS3 is tyrosine phosphorylated by c-Abl, and this modification is essential for the survival and tumorigenesis of specific cancer cells.
- These findings offer new perspectives on the oncogenic functions of Abl kinases.
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