Stanniocalcin-1 and -2: The insulin-like growth factor system and beyond

Stanniocalcin-1 and -2 (STC1 and STC2) are secreted, highly evolutionarily conserved proteins. STC1 was described more than 40 years ago in teleost fish and implicated in calcium regulation by unknown mechanisms. Soon thereafter, both of the stanniocalcins were reported in mammals, but it was discovered only 10 years ago that they are potent inhibitors of the pappalysin metalloproteinases PAPP-A and PAPP-A2. Through these interactions, STC1 and STC2 indirectly reduce the bioactivity of insulin-like growth factors (IGFs). Beyond this regulatory system, which has been delineated mechanistically at both the functional and structural levels, numerous studies published over the past decade have implicated the stanniocalcins in a wide range of biological processes, including immune modulation, mitochondrial stress responses, integrin engagement, DNA repair, and reproduction. However, the mechanistic evidence supporting these functions is generally less robust, and the reported effects are often context-dependent. This is particularly true for STC1, which can exert opposing effects depending on the cell type and biological context. Proposed intracellular and nuclear activities also raise unresolved questions regarding cellular uptake and trafficking. Defining where, when, and how STC1 and STC2 act is therefore essential for understanding their physiological roles in these processes. This review critically evaluates the molecular functions attributed to mammalian STC1 and STC2, with an emphasis on direct protein interactions and the extent to which proposed functions are supported by structural, biochemical, genetic, and functional evidence. Determining to what extent the diverse reported effects converge on shared mechanisms will be essential for developing a coherent understanding of stanniocalcin biology.