Protein Tyrosine Phosphatase SHP-2 Is Involved in the Interleukin-21-Induced Activation of Extracellular Signal-Regulated Kinase 1/2

Protein Tyrosine Phosphatase SHP-2 Is Involved in the Interleukin-21-Induced Activation of Extracellular Signal-Regulated Kinase 1/2

LIANJIN JIN,¹ HIDETOSHI NARA,¹ MIZANUR RAHMAN,¹ YUJI TAKEDA,¹ AKEMI ARAKI¹ and HIRONOBU ASAO¹

¹Department of Immunology, Yamagata University Faculty of Medicine, Yamagata, Yamagata, Japan

The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4⁺ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8⁺ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation.

keywords —— cell proliferation; cytokine; extracellular signal-regulated kinase 1/2; interleukin-21; SH2 domain-containing tyrosine phosphatase

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Tohoku J. Exp. Med., 2018, 244, 187-193

Correspondence: Hironobu Asao, Department of Immunology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, Yamagata 990-9585, Japan.

e-mail: asao-h@med.id.yamagata-u.ac.jp