Conditional deletion of Shp2 tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCR signals.
It is well known that T cell differentiation and maturation in the thymus is tightly controlled at multiple checkpoints. However, the molecular mechanism for the control of this developmental program is not fully understood. A number of protein tyrosine kinases, such as Zap-70, Lck, and Fyn, have been shown to promote signals required for thymocyte development, whereas a tyrosine phosphatase Src homology domain-containing tyrosine phosphatase (Shp)1 has a negative effect in pre-TCR and TCR signaling. We show in this study that Shp2, a close relative of Shp1, plays a positive role in T cell development and functions. Lck-Cre-mediated deletion of Shp2 in the thymus resulted in a significant block in thymocyte differentiation/proliferation instructed by the pre-TCR at the beta selection step, and reduced expansion of CD4(+) T cells. Furthermore, mature Shp2(-/-) T cells showed decreased TCR signaling in vitro. Mechanistically, Shp2 acts to promote TCR signaling through the ERK pathway, with impaired activation of ERK kinase observed in Shp2(-/-) T cells. Thus, our results provide physiological evidence that Shp2 is a common signal transducer for pre-TCR and TCR in promoting T cell maturation and proliferation.
Nguyen
Thanh V
TV
Programs in Signal Transduction and Stem Cells and Regeneration, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Ke
Yuehai
Y
Zhang
Eric E
EE
Feng
Gen-Sheng
GS
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000276:immunology*
D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse