Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID.
Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
S M
SM
Russell
J A
JA
Johnston
M
M
Noguchi
M
M
Kawamura
C M
CM
Bacon
M
M
Friedmann
M
M
Berg
D W
DW
McVicar
B A
BA
Witthuhn
O
O
Silvennoinen
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D009154:Mutation; D010766:Phosphorylation; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3