Abstract 2206: SOCS1 and SOCS3 attenuate Lck-mediated cellular transformation through distinct mechanisms

Abstract

Abstract The suppressor of cytokine signaling (SOCS) proteins are negative feedback inhibitors of Janus kinase (JAK) – signal transducer and activator of transcription (STAT) signaling in response to cytokine stimulation. Among eight SOCS family members, SOCS1, SOCS2, SOCS3 and CIS (cytokine-inducible SH2-containing protein) are best characterized both structurally and functionally. We showed previously that CIS, SOCS1 and SOCS3 were not expressed in Lck-transformed cells (Cell Signal 18:851; Int J Oncol 36:1201). It suggests that defective negative feedback control may contribute to constitutive JAK-STAT5 activation in Lck-mediated oncogenesis (J Immunol 159:5206; Mol Cancer Res 4:39). These findings also raise the possibility that SOCS proteins may function as tumor suppressors. Indeed, by enforced SOCS1 and SOCS3 expression, we were able to reduce Lck-induced cellular transformation (Int J Oncol 36:1201). In this report, we further examine the molecular mechanisms underlying SOCS tumor-suppressing activity. Through comparative studies of SOCS1, SOCS2, SOCS3 and CIS, we demonstrate here two distinct properties of SOCS1 and SOCS3 toward oncogenic Lck kinase. First, SOCS1 has the highest affinity in binding to oncogenic Lck kinase. We identified the positive regulatory phospho-tyrosine 394 residue (Y394) in the kinase domain as the key interacting determinant in Lck. Additionally, the Lck kinase domain alone is sufficient to bind SOCS1. While the SH2 domain in SOCS1 is important in its association with the oncogenic Lck kinase, other functional domains may also contribute to overall binding affinity. These data suggest that SOCS1 may inhibit Lck kinase activity in a manner similar to JAK kinases. Second, only SOCS3 becomes phosphorylated in the presence of oncogenic Lck kinase. We identified the phosphorylation sites as Y204 and Y221 located in the C-terminal SOCS box of SOCS3. We further analyzed the contribution of SOCS3 tyrosine phosphorylation on its tumor suppressor activity. Preliminary studies suggested that SOCS3 phosphorylation on Y204 and Y221 might play an important role in blocking cell proliferation and cell cycle progression of Lck-transformed cells. SOCS3 tyrosine phosphorylation can lead to altered protein stability and crosstalk with other signal transduction pathways, such as MAPK signaling. Experiments are in progress to further define the molecular details of SOCS3 phosphorylation involved in tumor suppression. All together, these results provide important mechanistic insights into the distinct roles of SOCS proteins as tumor suppressors in cells transformed by oncogenic protein tyrosine kinases. This work is supported in part by NIH grant CA107210. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2206. doi:10.1158/1538-7445.AM2011-2206