S Tsujino1, T Miyazaki, A Kawahara, M Maeda, T Taniguchi, H Fujii. 1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract
BACKGROUND: The interleukin-2 receptor (IL-2R) consists of three subunits, the IL-2Ralpha, IL-2Rbetac, and IL-2Rgammac chains. The essential role of the IL-2Rgammac cytoplasmic domain, consisting of 86 amino acids, in signal transmission has been well documented. Particularly, the carboxyl ter-minal region containing 48 amino acids. is essential for the association with and activation of the Jak3 protein tyrosine kinase. On the other hand, little is known about the role of the rest of the IL-2Rgammac cytoplasmic region consisting of the membrane-proximal 38 amino acids. RESULTS: We show that a truncated mutant form of IL-2Rgammac which lacks the membrane-distal 48 amino acids is still capable of inducing the activation of Jak1 and Stat3/Stat5 in the absence of Jak3 activation. This membrane-proximal region can also mediate the IL-2-induced tyrosine phosphorylation of the p85 subunit of phosphatidylinositol-3-kinase (PI3K). Furthermore, these signalling events are completely abrogated when mutations are introduced into the proline-rich motif in this region. CONCLUSIONS: In this study, we identified a Jak3-independent signalling pathway(s) from the membrane-proximal region of IL-2Rgammac. Our results indicate that the proline-rich motif in this region plays a critical role in this signalling pathway(s). The present study may provide further insight into the mechanism of cellular responses mediated by IL-2 and other cytokines which utilize the IL-2Rgammac for their signal transmission.
BACKGROUND: The interleukin-2 receptor (IL-2R) consists of three subunits, the IL-2Ralpha, IL-2Rbetac, and IL-2Rgammac chains. The essential role of the IL-2Rgammac cytoplasmic domain, consisting of 86 amino acids, in signal transmission has been well documented. Particularly, the carboxyl ter-minal region containing 48 amino acids. is essential for the association with and activation of the Jak3 protein tyrosine kinase. On the other hand, little is known about the role of the rest of the IL-2Rgammac cytoplasmic region consisting of the membrane-proximal 38 amino acids. RESULTS: We show that a truncated mutant form of IL-2Rgammac which lacks the membrane-distal 48 amino acids is still capable of inducing the activation of Jak1 and Stat3/Stat5 in the absence of Jak3 activation. This membrane-proximal region can also mediate the IL-2-induced tyrosine phosphorylation of the p85 subunit of phosphatidylinositol-3-kinase (PI3K). Furthermore, these signalling events are completely abrogated when mutations are introduced into the proline-rich motif in this region. CONCLUSIONS: In this study, we identified a Jak3-independent signalling pathway(s) from the membrane-proximal region of IL-2Rgammac. Our results indicate that the proline-rich motif in this region plays a critical role in this signalling pathway(s). The present study may provide further insight into the mechanism of cellular responses mediated by IL-2 and other cytokines which utilize the IL-2Rgammac for their signal transmission.
Authors: S Tsujino; J P Di Santo; A Takaoka; T L McKernan; S Noguchi; C Taya; H Yonekawa; T Saito; T Taniguchi; H Fujii Journal: Proc Natl Acad Sci U S A Date: 2000-09-12 Impact factor: 11.205
Authors: A Arcas-García; M Garcia-Prat; M Magallón-Lorenz; A Martín-Nalda; O Drechsel; S Ossowski; L Alonso; J G Rivière; P Soler-Palacín; R Colobran; J Sayós; M Martínez-Gallo; C Franco-Jarava Journal: Clin Exp Immunol Date: 2020-01-19 Impact factor: 4.330
Authors: Sathya D Unudurthi; Drew Nassal; Amara Greer-Short; Nehal Patel; Taylor Howard; Xianyao Xu; Birce Onal; Tony Satroplus; Deborah Hong; Cemantha Lane; Alyssa Dalic; Sara N Koenig; Adam C Lehnig; Lisa A Baer; Hassan Musa; Kristin I Stanford; Sakima Smith; Peter J Mohler; Thomas J Hund Journal: J Clin Invest Date: 2018-11-12 Impact factor: 14.808