Noggin proteins are multifunctional extracellular regulators of cell signalling

Noggin is an extracellular cysteine knot protein that plays a crucial role in vertebrate dorsoventral (DV) patterning. Noggin binds and inhibits the activity of bone morphogenetic proteins (BMPs) via a conserved N-terminal Clip domain. Non-canonical orthologs of Noggin that lack a Clip domain (“Noggin-like” proteins) are encoded in many arthropod genomes are thought to have evolved into receptor tyrosine kinase (RTK) ligands that promote Torso/RTK signalling rather than inhibiting BMP signalling. Here, we examined the molecular function of noggin/noggin-like genes (ApNL1 and ApNL2) from the arthropod pea aphid using the dorso-ventral patterning of Xenopus and the terminal patterning system Drosophila to identify whether these proteins function as BMP or RTK signalling regulators. Our findings reveal that ApNL1 from the pea aphid can regulate both BMP and RTK signalling pathways, and unexpectedly, that the Clip domain is not essential for its antagonism of BMP signalling. Our findings indicate that ancestral noggin/noggin-like genes were multifunctional regulators of signalling that have specialised to regulate multiple cell signalling pathways during the evolution of animals.