Critical role of the membrane-proximal, proline-rich motif of the interleukin-2 receptor gammac chain in the Jak3-independent signal transduction.
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.
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
S
S
Tsujino
T
T
Miyazaki
A
A
Kawahara
M
M
Maeda
T
T
Taniguchi
H
H
Fujii
D000595:Amino Acid Sequence; D001483:Base Sequence; D002461:Cell Line, Transformed; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008894:Milk Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011392:Proline; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3