Reciprocal Signaling Roles for STAT3 and SHP2

Abstract

One subunit of the interleukin-6 (IL-6) receptor, which activates Janus kinases upon ligand binding, is gp130. Tyrosine phosphorylation of gp130 recruits protein phosphatase 2 (SHP2) and signal transducer and activator 3 (STAT3). Ohtani et al . utilized knock-in technology to create mice deficient in only the gp130-mediated SHP2 pathway or the gp130-mediated STAT3 pathway to dissect the roles these two pathways play in IL-6 signaling. Eliminating the SHP2 response resulted in prolonged IL-6-induced STAT3 phosphorylation. STAT3 signaling was required for embryonic development, where as SHP2 signaling-deficient mice were viable and fertile. STAT3 signaling was required for induction of astrocytes by IL-6 cytokines. Reciprocal roles for STAT3 signaling and SHP2 signaling (STAT3 providing a positive signal and SHP2 providing a negative signal) were found for cytokine and immunoglobulin responses and lymphoid organ homeostasis. Thus, mice deficient in SHP2 signaling developed splenomegaly and lymphadenopathy, and demonstrated increased induction of acute phase proteins and increased antibody production by B cells in response to thymus dependent antigens. Ohtani, T., Ishahara, K., Atsumi, T., Nishida, K., Kaneko, Y., Miyata, T., Itoh, S., Narimatsu, M., Maeda, H., Fukada, T., Itoh, M., Okano, H., Hibi, M., and Hirano, T. (2000) Dissection of signaling cascades through gp130 in vivo: Reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity 12: 95-105. [Online Journal]