The Intersectin 2 Adaptor Links Wiskott Aldrich Syndrome Protein (WASp)-mediated Actin Polymerization to T Cell Antigen Receptor Endocytosis

doi:10.1084/jem.194.12.1777

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Published 17 December 2001. doi:10.1084/jem.194.12.1777

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© Rockefeller University Press, 0022-1007/2001/12/1777/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 12, December 17, 2001 1777-1787

Original Article

The Intersectin 2 Adaptor Links Wiskott Aldrich Syndrome Protein (WASp)-mediated Actin Polymerization to T Cell Antigen Receptor Endocytosis

Mary K.H. McGavin¹^,2^,3, Karen Badour¹^,2^,3, Lynne A. Hardy¹^,2^,3, Terrance J. Kubiseski³, Jinyi Zhang¹^,2^,3 and Katherine A. Siminovitch¹^,2^,3

¹ Department of Medicine, Department of Immunology, and Department of Medical and Molecular Genetics, University of Toronto, the
² Toronto General Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
³ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Address correspondence to K.A. Siminovitch, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada. Phone: 416-586-8723; Fax: 416-586-8731; E-mail: ksimin{at}mshri.on.ca

Induction of T cell antigen receptor (TCR) endocytosis has asignificant impact on TCR signaling and T cell behavior, butthe molecular interactions coordinating internalization of theactivated TCR are poorly understood. Previously we have shownthat TCR endocytosis is regulated by the Wiskott Aldrich Syndromeprotein (WASp), a cytosolic effector which, upon interactionwith the cdc42 Rho GTPase, couples TCR engagement to Arp 2/3complex-mediated actin polymerization. Here we report that WASpassociates in T cells with intersectin 2, an endocytic adaptorcontaining multiple domains including a Dbl homology (DH) domainwith the potential to activate Rho GTPases. Intersectin 2 associationwith WASp increases after TCR engagement, and its overexpressionin Cos-7 cells induces WASp translocation to endocytic vesicleswithin which intersectin 2 colocalizes with both WASp and cdc42.Intersectin 2, but not a DH domain-deleted ( ${Delta}$ DH) form of intersectin2, and stimulation via the TCR also trigger the activation ofcdc42. Induction of TCR internalization is also augmented byintersectin 2 and severely impaired by latrunculin B treatment.Thus, intersection 2 appears to function cooperatively withWASp and cdc42 to link the clathrin endocytic machinery to WASp-mediatedactin polymerization and ultimately to occupancy-induced TCRendocytosis.

Key Words: TCR endocytosis • actin polymerization • T cell activation • Wiskott Aldrich Syndrome protein • intersectin

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