A hallmark of multicellular organisms is that their cells can differentiate into different cell types, which in turn can proliferate, remain at a steady state or die. To direct the fates of cells multicellular organisms make use of on an intricate intercellular signaling network, composed of cytokines, receptors and pathway-specific transcription factors. Surprisingly, the number of players involved is relatively small, raising the question, how can a small number of signaling modes conspire to produce a result as complex as man? Tissue specific spatial and temporal order of expression is an important source of complexity, but additional layers are also derived from pathway-specific co-receptors or inhibitors. For example, the TGF-β family protein Nodal, which is essential for mesoderm formation and left-right patterning in the embryo, but also plays a devastating role in melanoma and breast cancer proliferation when it acts aberrantly, signals via the type I and type II receptors ALK-4 and ActRII, respectively. But additional extracellular proteins help regulate the pathway. Nodal signaling has been widely studied in vivo and its receptor interactions are understood in a general way from a large body of work on TGF-β family paralogs, but the molecular basis for Nodal regulation by other factors remains poorly understood
