The molecular role of the common gamma c subunit in signal transduction reveals functional asymmetry within multimeric cytokine receptor complexes.
The specific signal transduction function of the gamma c subunit in the interleukin (IL) 2, IL-4, IL-7, IL-9, and IL-15 receptor complexes remains undefined. The present structure-function analyses demonstrated that the entire cytoplasmic tail of gamma c could be functionally replaced in the IL-2 receptor (IL-2R) signaling complex by a severely truncated erythropoietin receptor cytoplasmic domain lacking tyrosine residues. Heterodimerization of IL-2R beta with either gamma c or the truncated erythropoietin receptor chain led to an array of specific signals normally derived from the native IL-2R despite the substitution of Janus kinase JAK2 for JAK3 in the receptor complex. These findings thus suggest a model in which the gamma c subunit serves as a common and generic "trigger" chain by providing a nonspecific Janus kinase for signaling program initiation, while signal specificity is determined by the unique "driver" subunit in each of the gamma c- containing receptor complexes. Furthermore, these results may have important functional implications for the asymmetric design of many cytokine receptor complexes and the evolutionary design of receptor subfamilies that share common trigger or driver subunits.
Lai
S Y
SY
Gladstone Institute of Virology and Immunology, San Francisco, CA 94141, USA.
Xu
W
W
Gaffen
S L
SL
Liu
K D
KD
Longmore
G D
GD
Greene
W C
WC
Goldsmith
M A
MA
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics; D018121:Receptors, Cytokine / Q000737:chemistry*; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000737:chemistry* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology
D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D011961:Receptors, Fc; D015375:Receptors, Interleukin-2; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053614:Janus Kinase 2; D053616:Janus Kinase 3