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Molecular and Cellular Biology, June 2009, p. 2997-3006, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01008-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Integrating Receptor Signal Inputs That Influence Small Rho GTPase Activation Dynamics at the Immunological Synapse{triangledown} ,{dagger}

Konstantina Makrogianneli,1,2,{ddagger} Leo M. Carlin,1,2,{ddagger} Melanie D. Keppler,1,2 Daniel R. Matthews,1,2 Enyinnaya Ofo,1,2 Anthony Coolen,3 Simon M. Ameer-Beg,1,2 Paul R. Barber,4 Borivoj Vojnovic,4 and Tony Ng1,2*

Richard Dimbleby Department of Cancer Research,1 Division of Cancer Studies and Randall Division of Cell & Molecular Biophysics, King's College London, Guy's Medical School Campus, London SE1 1UL, United Kingdom,2 Department of Mathematics, King's College London, Strand Campus, London WC2R 2LS, United Kingdom,3 University of Oxford, Gray Cancer Institute, Mount Vernon Hospital, Northwood HA6 2JR, United Kingdom4

Received 26 June 2008/ Returned for modification 6 November 2008/ Accepted 9 March 2009

The Rho GTPase Cdc42 regulates cytoskeletal changes at the immunological synapse (IS) that are critical to T-cell activation. By imaging fluorescent activity biosensors (Raichu) using fluorescence lifetime imaging microscopy, Cdc42 activation was shown to display kinetics that are conditional on the specific receptor input (through two IS-associated receptors, CD3 and β1 integrin). CD3-triggered Cdc42 activity is dependent on the cyto-2 (NPIY) motif of the β1 integrin cytoplasmic domain. Perturbations of the ezrin-radixin-moesin (ERM) function blocked CD3- and β1-dependent increases in Cdc42 activity. Both IS-associated receptors probably lie on a serial molecular pathway and transduce signals through the ERM-dependent machinery that is responsible for the remodeling and stabilization of the synapse. Cdc42 activity is impaired in β1 integrin-deficient T cells that form conjugates with antigen-presenting cells but is partially restored in the context of an antigen-specific synapse. This restoration of Cdc42 activity is due, at least in part, to the recruitment and activation of β2 integrin.

* Corresponding author. Mailing address: King's College London, 2nd Floor, New Hunt's House, Guy's Medical School Campus, London SE1 1UL, United Kingdom. Phone: 44 (0) 20 7848 8056. Fax: 44 (0) 20 7848 6435. E-mail: tony.ng{at}kcl.ac.uk

{triangledown} Published ahead of print on 23 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, June 2009, p. 2997-3006, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01008-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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