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Molecular and Cellular Biology, November 2006, p. 8655-8665, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00168-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Lck Regulates the Threshold of Activation in Primary T Cells, While both Lck and Fyn Contribute to the Magnitude of the Extracellular Signal-Related Kinase Response{triangledown}

Matthew Lovatt,1,{dagger} Andrew Filby,1 Valentino Parravicini,1 Guy Werlen,2,{ddagger} Ed Palmer,2 and Rose Zamoyska1*

Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, London NW71AA, United Kingdom,1 Laboratory of Transplantation Immunology and Nephrology, Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland2

Received 30 January 2006/ Returned for modification 28 February 2006/ Accepted 24 August 2006

The src family kinases p56lck (Lck) and p59fyn (Fyn) are the most proximal signaling molecules to be activated downstream of the T-cell receptor. Using an inducible transgenic model, we can regulate the expression of Lck in primary T cells and ask how the signaling cascade and differentiation potential are affected by the absence or the presence of reduced levels of Lck. We show that in naïve T cells, Lck controls the threshold of activation by preferentially regulating multiple signaling pathways that result in the mobilization of Ca2+ through activation of phospholipase C-gamma and protein kinase C as well as activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. Fyn is also able to stimulate the ERK/MAPK pathway in primary T cells but has little influence on the mobilization of Ca2+. Only Lck efficiently stimulates production of diacylglycerol and therefore RasGRP1 recruitment to the plasma membrane and phosphorylation of Shc, suggesting that Fyn activates ERK via a different upstream signaling route. Finally, we show that signals through Lck are essential for the development of T-cell-effector potential, particularly for effective cytokine transcription.

* Corresponding author. Mailing address: Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, London NW71AA, United Kingdom. Phone: 44-(0)20-8816-2466. Fax: 44-(0)20-8816-2248. E-mail: rzamoys{at}nimr.mrc.ac.uk.

{triangledown} Published ahead of print on 11 September 2006.

{dagger} Present address: Department of Immunobiology, King's College, London SE1 9RT, United Kingdom.

{ddagger} Present address: Rutgers University, Dept. of Cell Biol. and Neuroscience, Room B333, Piscataway, N.J.

Molecular and Cellular Biology, November 2006, p. 8655-8665, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00168-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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