Abstract
Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53-SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence. Mass spectrometry confirmed SOCS1 Y80 phosphorylation in cells, and a new mAb was generated to detect its presence in tissues by IHC. A tyrosine kinase library screen identified the SRC family as Y80-SOCS1 kinases. SRC family kinase inhibitors potentiated the SOCS1-p53 pathway and reinforced SOCS1-induced senescence. Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. Collectively, these results reveal a mechanism that inactivates the SOCS1-p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful. SIGNIFICANCE: These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.
Highlights
suppressor of cytokine signaling-1 (SOCS1) is a 211-amino acid protein composed of a central SH2 domain and a C-terminal domain called the SOCS box [1]
Samples from human lymphomas that often overexpress SOCS1 displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. These results reveal a mechanism that inactivates the SOCS1–p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful. These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors
Using GST pull-down assays and 35S-labeled SOCS1 produced by in vitro translation, we found that p53 interacts with SOCS1 via the TAD2 (Fig. 1A)
Summary
SOCS1 is a 211-amino acid protein composed of a central SH2 (src homology) domain and a C-terminal domain called the SOCS box [1]. The SH2 domain of SOCS1 recognizes target proteins that are ubiquitinated and targeted to the proteasome by the E3 ligase complex bound to the SOCS box [2]. SOCS1 binds to the tumor suppressor p53 but does not stimulate its degradation [3,4,5]. The SH2 domain of SOCS1 interacts with the N-terminal transactivation domain of p53, while the C-terminal domain of SOCS1, containing the SOCS Box, mediates interaction with the DNA damage– regulated kinases ATM/ATR. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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