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Sci. Signal., 18 May 2010
Vol. 3, Issue 122, p. ra38
[DOI: 10.1126/scisignal.2000500]


Editor's Summary

Keeping Osteoclasts in Check
Bone resorption is mediated by cells known as osteoclasts, which develop from myeloid precursor cells. Differentiation and activation of osteoclasts depend on the signaling of receptors whose responses are mediated by the adaptor protein DAP12. One such receptor is TREM2, which drives osteoclastogenesis; deficiencies in either DAP12 or TREM2 result in similar phenotypes. TREM2- and DAP12-dependent signaling also inhibits some Toll-like receptor (TLR)–dependent responses in macrophages, another myeloid cell type. Thus, the TREM2-DAP12 signaling axis may be both stimulatory and inhibitory; however, little is known about how DAP12 functions in these different contexts. Peng et al. found that ligation of TREM2 with a cross-linking antibody triggered DAP12-dependent osteoclastogenesis that required the recruitment of phosphatidylinositol 3-kinase (PI3K) to the TREM2-DAP12 signaling complex. This signaling pathway was inhibited by the Src homology 2 (SH2) domain–dependent recruitment to TREM2-DAP12 of the inositol phosphatase SHIP1, which prevented PI3K from binding to DAP12. In addition, signaling downstream of other receptors on osteoclasts differentially recruited SHIP1 to DAP12. The authors thus propose that the stimulatory or inhibitory nature of TREM2-DAP12 signaling is regulated by SHIP1.

Citation: Q. Peng, S. Malhotra, J. A. Torchia, W. G. Kerr, K. M. Coggeshall, M. B. Humphrey, TREM2- and DAP12-Dependent Activation of PI3K Requires DAP10 and Is Inhibited by SHIP1. Sci. Signal. 3, ra38 (2010).

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Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and {gamma}-Secretase-dependent Intramembranous Cleavage.
P. Wunderlich, K. Glebov, N. Kemmerling, N. T. Tien, H. Neumann, and J. Walter (2013)
J. Biol. Chem. 288, 33027-33036
   Abstract »    Full Text »    PDF »
A Physical Interaction Between the Adaptor Proteins DOK3 and DAP12 Is Required to Inhibit Lipopolysaccharide Signaling in Macrophages.
Q. Peng, C. L. Long, S. Malhotra, and M. B. Humphrey (2013)
Science Signaling 6, ra72
   Abstract »    Full Text »    PDF »
CD2AP/SHIP1 Complex Positively Regulates Plasmacytoid Dendritic Cell Receptor Signaling by Inhibiting the E3 Ubiquitin Ligase Cbl.
M. Bao, S. Hanabuchi, V. Facchinetti, Q. Du, L. Bover, J. Plumas, L. Chaperot, W. Cao, J. Qin, S.-C. Sun, et al. (2012)
J. Immunol. 189, 786-792
   Abstract »    Full Text »    PDF »
TREM2 and {beta}-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis.
K. Otero, M. Shinohara, H. Zhao, M. Cella, S. Gilfillan, A. Colucci, R. Faccio, F. P. Ross, S. L. Teitelbaum, H. Takayanagi, et al. (2012)
J. Immunol. 188, 2612-2621
   Abstract »    Full Text »    PDF »
The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses.
T. Nakano-Yokomizo, S. Tahara-Hanaoka, C. Nakahashi-Oda, T. Nabekura, N. K. Tchao, M. Kadosaki, N. Totsuka, N. Kurita, K. Nakamagoe, A. Tamaoka, et al. (2011)
J. Exp. Med. 208, 1661-1671
   Abstract »    Full Text »    PDF »
An ENU-induced mouse mutant of SHIP1 reveals a critical role of the stem cell isoform for suppression of macrophage activation.
N.-Y. N. Nguyen, M. J. Maxwell, L. M. Ooms, E. M. Davies, A. A. Hilton, J. E. Collinge, D. J. Hilton, B. T. Kile, C. A. Mitchell, M. L. Hibbs, et al. (2011)
Blood 117, 5362-5371
   Abstract »    Full Text »    PDF »
How ITAMs Inhibit Signaling.
L. B. Ivashkiv (2011)
Science Signaling 4, pe20
   Abstract »    Full Text »    PDF »
Inhibitory ITAM Signaling Traps Activating Receptors with the Phosphatase SHP-1 to Form Polarized "Inhibisome" Clusters.
S. Pfirsch-Maisonnas, M. Aloulou, T. Xu, J. Claver, Y. Kanamaru, M. Tiwari, P. Launay, R. C. Monteiro, and U. Blank (2011)
Science Signaling 4, ra24
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Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8.
S. Bhattacharyya, N. S. Balakathiresan, C. Dalgard, U. Gutti, D. Armistead, C. Jozwik, M. Srivastava, H. B. Pollard, and R. Biswas (2011)
J. Biol. Chem. 286, 11604-11615
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