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* Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; and
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263
The Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an important molecular intermediate in multiple signaling pathways governing immune cell function. In this study, we report that SLP-76 is expressed in CD11c+B220– dendritic cells (DCs) isolated from murine thymus or spleen, and that SLP-76 is rapidly phosphorylated on tyrosine residues upon plating of bone marrow-derived DCs (BMDCs) on integrin agonists. SLP-76 is not required for the in vitro or in vivo generation of DCs, but SLP-76-deficient BMDCs adhere poorly to fibronectin, suggesting impaired integrin function. Consistent with impaired adhesion, cutaneous SLP-76-deficient DCs leave ear tissue at an elevated frequency compared with wild-type DCs. In addition, the pattern and distribution of actin-based podosome formation are visibly altered in BMDCs lacking SLP-76 following integrin engagement. SLP-76-deficient BMDCs manifest multiple signaling defects following integrin ligation, including reduced global tyrosine phosphorylation and markedly impaired phosphorylation of p44/42 MAPK (ERK1/2). These data implicate SLP-76 as an important molecular intermediate in the signaling pathways regulating multiple integrin-dependent DC functions, and add to the growing body of evidence that hemopoietic cells may use unique molecular intermediates and mechanisms for regulating integrin signaling.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI54666 (to J.L.C.), Roswell Park Cancer Center Support Grant CA16056, and an Arthritis Foundation Investigator Award (to J.L.C.).
2 Address correspondence and reprint requests to Dr. James L. Clements, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: james.clements{at}roswellpark.org
3 Abbreviations used in this paper: DC, dendritic cell; BLNK, B cell linker protein; BMDC, bone marrow-derived DC; F-actin, filamentous actin; FAK, focal adhesion kinase; int, intermediate; LAT, linker for activation of T cells; PLC
1, phospholipase C1; PTK, protein tyrosine kinase; SLP-76, Src homology 2 domain-containing leukocyte protein of 76 kDa; WASp, Wiskott-Aldrich syndrome protein.
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