The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn.
IgE/antigen-dependent mast cell activation plays a central role in immediate hypersensitivity and other allergic reactions. The Src family tyrosine kinase (SFK) Lyn is activated by the cross-linking of high-affinity IgE receptors (FcepsilonRI). Activated Lyn phosphorylates the FcepsilonRI subunits, beta and gamma, leading to subsequent activation of various signaling pathways. Lyn also plays a negative regulatory function by activating negative regulatory molecules. Another SFK, Fyn, also contributes to mast cell degranulation by inducing Gab2-dependent microtubule formation. Here we show that a third SFK, Hck, plays a critical role in mast cell activation. Degranulation and cytokine production are reduced in FcepsilonRI-stimulated hck(-/-) mast cells. The reduced degranulation can be accounted for by defects in Gab2 phosphorylation and microtubule formation. Importantly, Lyn activity is elevated in hck(-/-) cells, leading to increased phosphorylation of several negative regulators. However, positive regulatory events, such as activation of Syk, Btk, JNK, p38, Akt, and NF-kappaB, are substantially reduced in hck(-/-) mast cells. Analysis of lyn(-/-)hck(-/-), lyn(-/-)FcepsilonRIbeta(-/-), and hck(-/-)FcepsilonRIbeta(-/-) cells shows that Hck exerts these functions via both Lyn-dependent and Lyn-independent mechanisms. Thus, this study has revealed a hierarchical regulation among SFK members to fine-tune mast cell activation.
Hong
Hong
H
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA.
Kitaura
Jiro
J
Xiao
Wenbin
W
Horejsi
Vaclav
V
Ra
Chisei
C
Lowell
Clifford A
CA
Kawakami
Yuko
Y
Kawakami
Toshiaki
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D009687:Nuclear Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051572:Proto-Oncogene Proteins c-hck / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000145:classification / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C498444:Dok2 protein, mouse; C403503:FAM107A protein, human; D051380:GRB2 Adaptor Protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases