Occupancy of lymphocyte membrane receptors activates receptor-linked kinases, phosphatases and adaptor molecules and, in a manner dependent on cytoskeleton remodeling, instigates gene expression. The mechanisms by which membrane signaling translate into different patterns of gene expression, and ultimately, different cell fates, are a fertile area of investigation. Under the aegis of this grant, we have recently isolated and begun to characterize the function of a coactivator-like protein, Shn-3, that is situated immediately downstream of several T and B cell membrane receptors. The zinc finger protein Kappa Recognition Component (KRC), also known as Schnurri-3 (Shn-3), is a mammalian homologue of Drosophila schnurri. Two other mammalian Schnurri proteins have been isolated one of which, Schnurri2 (Shn-2) plays a role in thymocyte development. Not surprisingly, the signaling pathways involved with Schnurri proteins in mammalian cells have expanded when compared to the fly. We now know that Shn-3 is downstream of several lymphocyte membrane receptors, including TNFR, TCR and TGFaR. Upon TNFR signaling, Shn-3 associates with the adaptor protein TRAF2 to inhibit NFkappaB and JNK-dependent gene expression. Upon TCR stimulation, Shn-3 expression is rapidly induced and Shn-3 physically associates with the c-Jun transcription factor to augment AP-1 dependent gene transcription. Shn-3 KO T cells have impaired production of AP-1-dependent genes such as CD69 and IL-2. Upon TCR stimulation Shn-3 also associates with the Th2-specific transcription factor GATA-3, and T cells lacking Shn-3 have impaired production of GATA-3 dependent Th2 cytokines, IL- 4, IL-5 and IL-13. Finally, upon TGFa receptor signaling, Shn-3 physically associates with the transcription factor SMAD3 to inhibit IgA germline transcription in B cells;Shn-3 KO B cells have impaired IgA production and germline Iga gene transcription. Shn-3 thus appears to be a key adaptor protein for several membrane receptor pathways but the mechanisms by which it acts to modulate gene expression remain unknown. In selecting which of our observations to pursue further, we have been guided by the phenotype of the Shn-3 KO mouse. The most pronounced immune system abnormalities of these mice are evidence of impaired TGFbR signaling in B cells and impaired early development of the T helper 2 (Th2) lineage from its progenitor (Thp). In the next funding period we will: 1) investigate the function of Shn-3 in B cells and its relationship to TGFb receptor signaling, 2) investigate how Shn-3 regulates Th2 cell function, 3) establish the mechanisms by which Shn-3 functions to control gene expression and 4) explore the relationship between Shn-3 and Shn-2.
| Staton, Tracy L; Lazarevic, Vanja; Jones, Dallas C et al. (2011) Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472:105-9 |
| Greenblatt, Matthew B; Shim, Jae-Hyuck; Glimcher, Laurie H (2010) TAK1 mediates BMP signaling in cartilage. Ann N Y Acad Sci 1192:385-90 |
| Shim, Jae-Hyuck; Greenblatt, Matthew B; Xie, Min et al. (2009) TAK1 is an essential regulator of BMP signalling in cartilage. EMBO J 28:2028-41 |
| Glimcher, Laurie H; Jones, Dallas C; Wein, Marc N (2007) Control of postnatal bone mass by the zinc finger adapter protein Schnurri-3. Ann N Y Acad Sci 1116:174-81 |
| Jones, Dallas C; Wein, Marc N; Glimcher, Laurie H (2007) Schnurri-3 is an essential regulator of osteoblast function and adult bone mass. Ann Rheum Dis 66 Suppl 3:iii49-51 |
| Jones, Dallas C; Wein, Marc N; Oukka, Mohamed et al. (2006) Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Science 312:1223-7 |
| Pai, Sung-Yun; Truitt, Morgan L; Ho, I-Cheng (2004) GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci U S A 101:1993-8 |
| Lugo-Villarino, Geanncarlo; Maldonado-Lopez, Roberto; Possemato, Richard et al. (2003) T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells. Proc Natl Acad Sci U S A 100:7749-54 |
| Pai, Sung-Yun; Truitt, Morgan L; Ting, Chao-Nan et al. (2003) Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19:863-75 |
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