The role of Tsukushi as an extracellular signaling coordinator

Temporal and spatial coordination of multiple signaling pathways is essential for finely tuned cellular regulation in development. Extracellular signaling molecules that function in a concentration-dependent manner, collectively called morphogens, and their inhibitors both play pivotal roles in the regulation of embryogenesis. Understanding concerning the coordination of these signal molecule-dependent pathways has been mainly about the mechanisms of intracellular crosstalk. Small leucine-rich proteoglycan (SLRP) family proteins modulate various cellular processes, that is, cellular proliferation, growth, differentiation, survival, and adhesion. In this chapter, I discuss signal coordination at the extracellular level by this family of proteins that interact with a variety of signaling molecules, as exemplified by Tsukushi (TSK). We discovered a novel SLRP family member, TSK, which is expressed and secreted in several specific tissue areas where embryonic organogenesis is ongoing. TSK binds nodal/Vg1/TGF-β1, BMP4/chordin, FGF8, Frizzled4, and Delta and modulates their downstream intracellular signaling pathways, indicating multiple regulatory functions of TSK during development.