Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling

• Expression of SOCS2 is elevated in acute myeloid leukemia (AML).
• SOCS2 associates with FLT3 in response to FLT3 ligand stimulation in AML cell lines.
• SOCS2 interacts with FLT3 through FLT3 phosphotyrosine residues and SOCS2 SH2 domain.
• SOCS2 increases ubiquitination and degradation of FLT3.
• SOCS2 inhibits FLT3 signaling and FLT3-ITD-mediated transformation of cells.

The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family of E3 ubiquitin ligases. SOCS2 is known to regulate signal transduction by cytokine receptors and receptor tyrosine kinases. The receptor tyrosine kinase FLT3 is of importance for proliferation, survival and differentiation of hematopoietic cells and is frequently mutated in acute myeloid leukemia. We observed that SOCS2 associates with activated FLT3 through phosphotyrosine residues 589 and 919, and co-localizes with FLT3 in the cell membrane. SOCS2 increases FLT3 ubiquitination and accelerates receptor degradation in proteasomes. SOCS2 negatively regulates FLT3 signaling by blocking activation of Erk 1/2 and STAT5. Furthermore, SOCS2 expression leads to a decrease in FLT3-ITD-mediated cell proliferation and colony formation. Thus, we suggest that SOCS2 associates with activated FLT3 and negatively regulates the FLT3 signaling pathways.