SH2 domain-containing phosphatase-2 protein-tyrosine phosphatase promotes Fc epsilon RI-induced activation of Fyn and Erk pathways leading to TNF alpha release from bone marrow-derived mast cells.
Clustering of the high affinity IgE receptor (Fc(epsilon)RI) in mast cells leads to degranulation and production of numerous cytokines and lipid mediators that promote allergic inflammation. Initiation of FFc(epsilon)RI signaling involves rapid tyrosine phosphorylation of Fc(epsilon)RI and membrane-localized adaptor proteins that recruit additional SH2 domain-containing proteins that dynamically regulate downstream signaling. SH2 domain-containing phosphatase-2 (SHP2) is a protein-tyrosine phosphatase implicated in Fc(epsilon)RI signaling, but whose function is not well defined. In this study, using a mouse model allowing temporal shp2 inactivation in bone marrow-derived mast cells (BMMCs), we provide insights into SHP2 functions in the Fc(epsilon)RI pathway. Although no overt defects in Fc(epsilon)RI-induced tyrosine phosphorylation were observed in SHP2 knock-out (KO) BMMCs, several proteins including Lyn and Syk kinases displayed extended phosphorylation kinetics compared with wild-type BMMCs. SHP2 was dispensable for Fc(epsilon)RI-induced degranulation of BMMCs, but was required for maximal activation of Erk and Jnk mitogen-activated protein kinases. SHP2 KO BMMCs displayed several phenotypes associated with reduced Fyn activity, including elevated phosphorylation of the inhibitory pY531 site in Fyn, impaired signaling to Grb2-associated binder 2, Akt/PKB, and IkappaB kinase, and decreased TNF-alpha release compared with control cells. This is likely due to elevated Lyn activity in SHP2 KO BMMCs, and the ability of Lyn to antagonize Fyn activity. Overall, our study identifies SHP2 as a positive effector of Fc(epsilon)RI-induced activation of Fyn/Grb2-associated binder 2/Akt and Ras/Erk pathways leading to TNF-alpha release from mast cells.
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Victor A
VA
McPherson
Namit
N
Sharma
Stephanie
S
Everingham
Julie
J
Smith
Helen H
HH
Zhu
Gen-Sheng
GS
Feng
Andrew W B
AW
Craig
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D055785:Gene Knockdown Techniques; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism* / Q000502:physiology; D017455:Receptors, IgE / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D018909:src Homology Domains / Q000276:immunology
D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse