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Molecular and Cellular Biology, January 2008, p. 630-641, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00150-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The SH3 Domain of Lck Modulates T-Cell Receptor-Dependent Activation of Extracellular Signal-Regulated Kinase through Activation of Raf-1{triangledown}

Manqing Li,1,{dagger} Su Sien Ong,1 Bartek Rajwa,2 Vivian T. Thieu,3,{ddagger} Robert L. Geahlen,1 and Marietta L. Harrison1*

Department of Medicinal Chemistry and Molecular Pharmacology,1 Purdue University Cytometry Laboratories Bindley Bioscience Center,2 Department of Biochemistry, Purdue University, West Lafayette, Indiana 479073

Received 25 January 2007/ Returned for modification 23 February 2007/ Accepted 25 October 2007

Engagement of the T-cell antigen receptor (TCR) results in the proximal activation of the Src family tyrosine kinase Lck. The activation of Lck leads to the downstream activation of the Ras/Raf/MEK/ERK signaling pathway (where ERK is extracellular signal-related kinase). Under conditions of weak, but not strong, stimulation through the TCR, a version of Lck that contains a single point mutation in the SH3 (Src homology 3) domain (W97ALck) fails to support the activation of ERK, despite initiating signaling through the TCR, as demonstrated by the robust activation of ZAP-70, PLC-{gamma}, and Ras. We determined that the signaling lesion in W97ALck-expressing cells lies at the level of Raf-1 activation and is dependent on the presence of tyrosines 340/341 in the Raf-1 sequence. These data demonstrate a second function for Lck in TCR-mediated signaling to ERK. Additionally, we found that a significant fraction of Lck is localized to the Golgi apparatus and that, compared with wild-type Lck, W97ALck displays aberrant Golgi membrane localization. Our results support a model where under conditions of weak stimulation through the TCR, in addition to activated Ras, Golgi apparatus-localized Lck is needed for the full activation of Raf-1.

* Corresponding author. Mailing address: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Hansen Life Sciences Building, 201 South University Street, West Lafayette, IN 47907. Phone: (765) 494-1442. Fax: (765) 494-9193. E-mail: harrisonm{at}purdue.edu

{triangledown} Published ahead of print on 12 November 2007.

{dagger} Present address: Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA.

{ddagger} Present address: Department of Pediatrics, School of Medicine, Indiana University, Indianapolis, IN.

Molecular and Cellular Biology, January 2008, p. 630-641, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00150-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Falahati, R., Leitenberg, D. (2008). Selective Regulation of TCR Signaling Pathways by the CD45 Protein Tyrosine Phosphatase during Thymocyte Development. J. Immunol. 181: 6082-6091 [Abstract] [Full Text]  


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