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ShcA Mediates the Dominant Pathway to Extracellular Signal-Regulated Kinase Activation during Early Thymic Development ^,

Carter Immunology Center,¹ Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908²

Received 3 June 2006/ Returned for modification 2 August 2006/ Accepted 1 September 2006

During thymic development, the ß selection checkpoint is regulated by pre-T-cell receptor-initiated signals. Progression through this checkpoint is influenced by phosphorylation and activation of the serine/threonine kinases extracellular signal-regulated kinase 1 (ERK1) and ERK2, but the in vivo relevance of specific upstream players leading to ERK activation is not known. Here, using mice with a conditional loss of the shc1 gene or expressing mutants of ShcA, we demonstrate that the adapter protein ShcA is responsible for up to 70% of ERK activation in double-negative (DN) thymocytes in vivo and ex vivo. We also identify two specific tyrosines on ShcA that promote ERK phosphorylation in vivo, and mice expressing ShcA with mutations of these tyrosines show impaired DN thymocyte development. This work provides the first in vivo demonstration of the relative requirement of upstream adapters in controlling ERK activation during ß selection and suggests a dominant role for ShcA.

Published ahead of print on 18 September 2006.

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