Ecsit-ement on the crossroads of Toll and BMP signal transduction.

Elucidation of signaling networks and their specialized functions in different cell types represents a challenging scientific question. Establishment of signaling crosstalk between different pathways relies on biochemical evidence coupled to genetic analysis of key components of the pathways at stake, and definition of the epistatic relationships between such components. A new key contribution to the building of ever increasingly complex signal transduction networks appears in this issue of Genes & Development by Xiao et al. (2003). Using a combination of genetic analysis in the mouse and in vitro biochemical experiments in mammalian cells, those authors established that the adaptor protein Ecsit represents a signaling node intersecting the pathways downstream of Toll-like receptors (TLRs) and receptors for transforming growth factor(TGF) superfamily members. Toll-like signal transduction initiates at the cell surface by extracellular ligands, such as the Drosophila Spatzle protein, which upon physiological activation by extracellular proteases leads to proper dorsoventral patterning during early embryogenesis (Morisato and Anderson 1995). Alternatively, pathophysiological activation of Spatzle by fungal pathogens in adult Drosophila leads to innate immune responses (Takeda et al. 2003). Similar responses are induced by mammalian TLRs, which recognize a large variety of collectively known pathogen-associated molecular patterns (PAMPs), abundant in viruses, bacteria, fungi, and drugs. Both embryonic and adult Toll-like pathways lead to activation of the NFB family of transcription factors, critical regulators of dorsoventral patterning, but also of inflammatory cytokines and mediators of the innate immune response (Ghosh and Karin 2002). In addition, TLR signaling can activate the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways leading to additional gene regulatory inputs, whereas specialized TLR members can activate interferon regulatory factors (IRFs) that induce interferon gene expression, another critical factor of the immune response (Akira 2003). The TGFsuperfamily of cytokines, which includes TGFs as well as bone morphogenetic proteins (BMPs), is involved in the specification of embryonic patterning and in adult tissue homeostasis (Piek et al. 1999). TGFmembers regulate proliferation, differentiation, migration, and programmed death of diverse cell types, including mediators of innate and adaptive immunity (Letterio and Roberts 1998; McCartney-Francis et al. 1998; ten Dijke et al. 2002). These cellular responses are mediated by binding of the extracellular ligands to cell surface receptor serine/threonine kinases, whereby the Smad family of signal transducers are activated and translocated to the nucleus to control expression of target genes (Shi and Massague 2003). Additional signaling cascades, including Erk, JNK, and p38 MAPK pathways may also be activated by TGFmembers, and modulate the output of the Smad pathway (Derynck and Zhang 2003). The findings of Xiao et al. (2003) provide a new molecular link between TLR and BMP signaling pathways, involving the adaptor protein Ecsit. Ecsit seems to participate in a specific branch of the TLR signaling cascade that activates JNK or p38 MAPK (Kopp et al. 1999). The new work places Ecsit into the BMP pathway and enhances the accumulating evidence for common signaling mediators of the two evolutionarily conserved pathways. Such points of physical and functional contact between TLR and TGF/BMP signal transduction include, in addition to Ecsit, the TGF-activated kinase 1 (TAK1) protein complex, JNK and p38 MAPK, the IRFs, NFB, and Smads.