The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines.
Interleukin (IL)-2, a critical cytokine with indispensable functions in regulating lymphoid homeostasis, induces the activation of several biochemical pathways. Precisely how these pathways are linked and how they relate to the biological action of IL-2 is incompletely understood. We previously identified SHP-2 (Src homology 2 domain containing phosphatase 2) as an important intermediate in IL-2-dependent MAPK activation and showed its association with a 98-kDa phosphoprotein in response to IL-2. Here, we demonstrate that Gab2, a recently identified adapter molecule, is the major SHP-2 and phosphatidylinositol 3'-kinase-associated 98-kDa protein in normal, IL-2-activated lymphocytes. We further demonstrate that phosphorylation of both Gab2 and SHP-2 is largely dependent upon tyrosine 338 of the IL-2 receptor beta chain. Gab2 can be a substrate of all the three major classes of non-receptor tyrosine kinases associated with the IL-2R, but in terms of IL-2 signaling, JAK3 but not Lck or Syk is essential for Gab2 phosphorylation. We also demonstrate that only IL-2 and IL-15, but not other gammac cytokines induce Gab2 phosphorylation; the ability to phosphorylate Gab2 correlates with Shc phosphorylation and ERK1/ERK2 activation. Finally, we also show that Gab2 levels are regulated by T cell activation, and resting T cells express little Gab2. Therefore, up-regulation and activation of Gab2 may be important in linking the IL-2 receptor to activation of MAPK and may be an important means of achieving specificity in cytokine signaling.
Gadina
M
M
Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA. massimog@helix.nih.gov
Sudarshan
C
C
Visconti
R
R
Zhou
Y J
YJ
Gu
H
H
Neel
B G
BG
O'Shea
J J
JJ
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis*; D010766:Phosphorylation; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D010750:Phosphoproteins; D015375:Receptors, Interleukin-2; D020928:Mitogen-Activated Protein Kinases