Integrating receptor signal inputs that influence small Rho GTPase activation dynamics at the immunological synapse

Makrogianneli, K., Carlin, L. M. , Keppler, M. D., Matthews, D. R., Ofo, E., Coolen, A., Ameer-Beg, S. M., Barber, P. R., Vojnovic, B. and Ng, T. (2009) Integrating receptor signal inputs that influence small Rho GTPase activation dynamics at the immunological synapse. Molecular and Cellular Biology, 29(11), pp. 2997-3006. (doi: 10.1128/MCB.01008-08) (PMID:19307303) (PMCID:PMC2682016)

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Abstract

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.

Item Type:Articles
Additional Information:K. Makrogianneli is supported by a joint research studentship from MRC/King’s College London. L. Carlin and D. Matthews are supported by a United Kingdom EPSRC grant (EP/C546105/1). Enyinnaya Ofo is a recipient of both a Wellcome Trust Clinical Training Fellowship and the Dimbleby Cancer Care Award. M. Keppler, S. Ameer-Beg, and T. Ng are supported by an endowment fund from Dimbleby Cancer Care to King’s College London. A. Coolen is the recipient of a Springboard Research Fellowship from EPSRC. The multiphoton FLIM system was built with support from both the Medical Research Council Co-Operative Group grant (G0100152 ID 56891) and an United Kingdom Research Councils Basic Technology Research Programme grant (GR/R87901/01).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Carlin, Dr Leo
Authors: Makrogianneli, K., Carlin, L. M., Keppler, M. D., Matthews, D. R., Ofo, E., Coolen, A., Ameer-Beg, S. M., Barber, P. R., Vojnovic, B., and Ng, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Molecular and Cellular Biology
Publisher:American Society for Microbiology
ISSN:0270-7306
ISSN (Online):1098-5549

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