15 Regulation of the Smad Pathway by Signaling Cross-Talk

The TGF-β family of cytokines regulates a wide array of biological activities in various cell types and at different developmental stages. Smad proteins are critical mediators of TGF-β, BMP (bone morphogenetic protein), and activin signaling (Itoh et al. 2000; Moustakas et al. 2001; Derynck and Zhang 2003; Shi and Massague 2003). Upon phosphorylation by the active type I receptor kinase, R-Smads (receptor-activated Smads) form a heteromeric complex with the co-Smads (common-mediator Smads) and translocate into the nucleus, where they interact with sequence-specific DNA-binding cofactors and transcriptional coactivators or corepressors to regulate the expression of target genes (see Chapter 9). This pathway is integrated into the overall signaling network in the cell through cross-talk with other signaling pathways at multiple levels, which depend on the specific physiological context. These cross-talk activities play important roles in the regulation of various biological responses induced by TGF-β, BMP, or activin. In this chapter, the cross-talk of Smads with Wnt signaling, Notch signaling, MAP kinase signaling, phosphatidylinositol-3 (PI3) kinase-Akt, protein kinase C (PKC), and Jak-Stat pathway will be discussed. CROSS-TALK WITH WNT SIGNALING PATHWAY Combinatorial signaling often occurs in early embryos to allow overlapping signaling pathways to specify different territories and cell fates. The Wnt, BMP and TGF-β, and the Notch signaling pathways are integrated in this combinatorial signaling and often function in a synergistic or antagonistic manner to regulate vertebrate development. The Wnt signaling pathway has an important role in cell fate determination, self-renewal and maintenance of stem cell and early progenitor cells at...