Fig. 6. Shn proteins contribute to Bmp signaling by functioning as scaffolding factors. Shn proteins provide a framework that integrates Smads, co-activators/co-repressors and other transcription factors. The large size of Shn proteins may provide the flexibility to recognize different partners and to act through a variety of cis-elements. On genes such as Xvent2, Id3, brk, bam and gsb, that contain the GRCKNC(N5)GTCTG consensus, Smad1/Mad and Smad4/Med bind to GRCKNC and GTCT sites, probably as a heterotrimeric complex (Gao et al., 2005) (not represented in this figure). Shn/Shn1 interaction with the MH2 domains of Smads could stabilize the complex and provide docking sites for cell/tissue-specific co-repressors, as in A, or co-activators, as in B. Shn binding in A and B is highly sensitive to the spacing between the Smad sites indicating steric constraints (Gao et al., 2005; Pyrowolakis et al., 2004). (C) Shn promotes activation of Ubx in the Drosophila midgut through a promoter element that contains sites for Mad and an NFB-like site directly bound by Shn. In this context, there is no apparent requirement for Med binding to DNA. (D) In contrast, the mouse PPAR enhancer that is activated by Shn2 requires sites for Smad4 and C/EBP, but does not contain Smad1 motifs (Jin et al., 2006). The sensitivity of these enhancers to alterations in spacing between binding sites has not been tested.