Ecsit-ement on the crossroads of Toll and BMP signal transduction
- Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden
This extract was created in the absence of an abstract.
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-β (TGF-β) superfamily members.
Toll-like signal transduction initiates at the cell surface by extracellular ligands, such as the Drosophila Spätzle protein, which upon physiological activation by extracellular proteases leads to proper dorsoventral patterning during early embryogenesis (Morisato and Anderson 1995). Alternatively, pathophysiological activation of Spätzle 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 NF-κB 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 TGF-β superfamily of cytokines, which includes TGF-βs as well …
