Lawrence S. Mathews
The goals of this laboratory are to characterize the cell surface receptors and intracellular signaling mechanisms which mediate the actions of activin and related growth and differentiation factors. Activin A is a homodimeric protein which has been implicated in the control of diverse biological responses, including regulation of pituitary hormone expression, gonadal function, neural survival and signaling, erythropoiesis, and embryonic development.
We have identified receptors for activin by binding and chemically cross-linking radiolabeled activin to cells, leading to the characterization of two classes of binding proteins, the type I and type II receptors. Using a strategy based on expression in mammalian tissue culture cells, we obtained a cDNA clone for a type II activin receptor (ActRII). By using nucleic acid hybridization and PCR, we have identified a second type II receptor (ActRIIB) and a type I receptor (ActRI). Functional involvement of these molecules in activin signaling has been demonstrated by overexpression of ActRs both in Xenopus embryos, which leads to specific alterations in the pattern of embryonic differentiation, and in cultured cells.
The ActRs are transmembrane, ligand-activated protein serine kinases and are the prototypic members of a new subfamily of protein kinases that are receptors for activin-related molecules, including transforming growth factor b (TGFb). Biochemical analysis of the mechanism of activation of the activin receptors suggests that ligand binds specifically to receptor II, resulting in the recruitment of receptor I into the ligand-receptor complex. Following complex formation, receptor II phosphorylates receptor I at a specific glycine/serine rich site; that phosphorylation is required for intracellular signaling to occur. Very little is known about the signal transduction pathways activated by this family of ligands - the unique structure of the receptors suggests that those pathways may be as yet uncharacterized.
Research projects focus on:
- characterization of the interaction between type I and type II activin receptors, and of the regulation of ActR kinase activity,
- identification and cloning of intracellular targets for the ActR kinases,
- elucidation of the intracellular signaling pathways activated by ligand binding, and
- functional study of the role of receptors and substrates in mediating activin signals.