The Src homology 2 domain-containing leukocyte protein of 76-kDa adaptor links integrin ligation with p44/42 MAPK phosphorylation and podosome distribution in murine dendritic cells.
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.
Luckashenak
Nancy A
NA
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Ryszkiewicz
Rebecca L
RL
Ramsey
Kimberley D
KD
Clements
James L
JL
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D022081:Cell Surface Extensions / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D006413:Hematopoietic System / Q000166:cytology; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3