The Ly49 and KIR families are comprised of both inhibitory and activating receptors; the latter interacting and signaling through DAP12. We have continued our dissection of the proximal events associated with DAP12 signaling over the review period. The result of this work includes the definition of an apparent defect in DAP12 signaling in mice of the 129/Sv background that can profoundly effect the analysis of gene targeted mice, delineation of two levels of regulation of DAP12 signaling by CD45 (signal initiation and dephosphorylation of DAP-12 itself), and most recently, dissection of the overlapping use of the non-catalytic adaptor proteins Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB). TREM-1 regulates sepsis whereas TREM-2 can control the development of DC, microglia and osteoclasts. Our studies of the TREM cluster have led to publications regarding; 1) the identification of TREM-like transcript-1 (TLT-1), a protein that does not couple to DAP-12 but instead interacts with SHP-1; 2) characterization of TLT-1 as a platelet specific receptor sequestered in alpha granules; and 3) identification of soluble TLT-1 in serum, and solution of the crystal structure of the extracellular domain. We have also targeted TLT-1 in mice, shown its role in platelet aggregation in vitro, and defined some proteins that interact with it. Although platelets and thrombosis can regulate inflammation, cancer growth and metastasis, and adaptive immunity, we have chosen not to propose further TLT-1 studies under our base allocation here. If however, sufficient resources were available, we would continue biochemical study of TLT-1. We are currently, evaluating our TLT-1-/- mice in collaboration with a former fellow from our lab.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010300-09
Application #
7338380
Study Section
(LEI)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Gattis, James L; Washington, A Valance; Chisholm, Maia M et al. (2006) The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment. J Biol Chem 281:13396-403
Mason, Llewellyn H; Willette-Brown, Jami; Taylor, Lynn S et al. (2006) Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45. J Immunol 176:6615-23
Mason, L H; Willette-Brown, J; Mason, A T et al. (2000) Interaction of Ly-49D+ NK cells with H-2Dd target cells leads to Dap-12 phosphorylation and IFN-gamma secretion. J Immunol 164:603-11
Taylor, L S; Paul, S P; McVicar, D W (2000) Paired inhibitory and activating receptor signals. Rev Immunogenet 2:204-19
Paul, S P; Taylor, L S; Stansbury, E K et al. (2000) Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2. Blood 96:483-90
Ortaldo, J R; Winkler-Pickett, R; Willette-Brown, J et al. (1999) Structure/function relationship of activating Ly-49D and inhibitory Ly-49G2 NK receptors. J Immunol 163:5269-77
Makrigiannis, A P; Gosselin, P; Mason, L H et al. (1999) Cloning and characterization of a novel activating Ly49 closely related to Ly49A. J Immunol 163:4931-8
Gosselin, P; Mason, L H; Willette-Brown, J et al. (1999) Induction of DAP12 phosphorylation, calcium mobilization, and cytokine secretion by Ly49H. J Leukoc Biol 66:165-71
Taylor, L S; McVicar, D W (1999) Functional association of FcepsilonRIgamma with arginine(632) of paired immunoglobulin-like receptor (PIR)-A3 in murine macrophages. Blood 94:1790-6