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Sci. Signal., 13 November 2012
Vol. 5, Issue 250, p. ra82
[DOI: 10.1126/scisignal.2003113]

RESEARCH ARTICLES

The Tetraspanin CD37 Orchestrates the α4β1 Integrin–Akt Signaling Axis and Supports Long-Lived Plasma Cell Survival

Annemiek B. van Spriel1, Sandra de Keijzer1, Alie van der Schaaf1, Kate H. Gartlan2, Mariam Sofi2, Amanda Light3, Peter C. Linssen4, Jan B. Boezeman4, Malou Zuidscherwoude1, Inge Reinieren-Beeren1, Alessandra Cambi1, Fabienne Mackay2, David M. Tarlinton3, Carl G. Figdor1*{dagger}, and Mark D. Wright2*

1 Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen 6525 GA, Netherlands.
2 Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, VIC 3005, Australia.
3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia.
4 Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen 6500 HB, Netherlands.

* These authors contributed equally to this work.

Abstract: Signaling by the serine and threonine kinase Akt (also known as protein kinase B), a pathway that is common to all eukaryotic cells, is central to cell survival, proliferation, and gene induction. We sought to elucidate the mechanisms underlying regulation of the kinase activity of Akt in the immune system. We found that the four-transmembrane protein CD37 was essential for B cell survival and long-lived protective immunity. CD37-deficient (Cd37–/–) mice had reduced numbers of immunoglobulin G (IgG)–secreting plasma cells in lymphoid organs compared to those in wild-type mice, which we attributed to increased apoptosis of plasma cells in the germinal centers of the spleen, areas in which B cells proliferate and are selected. CD37 was required for the survival of IgG-secreting plasma cells in response to binding of vascular cell adhesion molecule 1 to the α4β1 integrin. Impaired α4β1 integrin–dependent Akt signaling in Cd37–/– IgG-secreting plasma cells was the underlying cause responsible for impaired cell survival. CD37 was required for the mobility and clustering of α4β1 integrins in the plasma membrane, thus regulating the membrane distribution of α4β1 integrin necessary for activation of the Akt survival pathway in the immune system.

{dagger} To whom correspondence should be addressed. E-mail: c.figdor{at}ncmls.ru.nl

Citation: A. B. van Spriel, S. de Keijzer, A. van der Schaaf, K. H. Gartlan, M. Sofi, A. Light, P. C. Linssen, J. B. Boezeman, M. Zuidscherwoude, I. Reinieren-Beeren, A. Cambi, F. Mackay, D. M. Tarlinton, C. G. Figdor, M. D. Wright, The Tetraspanin CD37 Orchestrates the α4β1 Integrin–Akt Signaling Axis and Supports Long-Lived Plasma Cell Survival. Sci. Signal. 5, ra82 (2012).

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882