Center for Bone Biology

PTH and IGF1 exert their anabolic effect on bone formation via regulating the phosphorylation of ATF4.

Xiaodan Wang.  Our preliminary studies suggested that insulin-like growth factor 1 (IGF1) enhances the phosphorylation of both RSK2 and ATF4.  It has been shown also by others that parathyroid hormone (PTH) induces the binding of OSE1 by an osteoblast nuclear protein, presumably ATF4.  It is well-known that PTH activates the protein kinase A (PKA) signaling pathway and we recently found that (i) the serine 254 of ATF4 is phosphorylated in response to PKA activation and (ii) this phosphorylation enhances its transactivation activity.  Based on these observations, we hypothesize that IGF1 and PTH execute their anabolic actions on bone formation through phosphorylation of ATF4 in osteoblasts, but do so by different pathways.  This project is to determine whether IGF1 and PTH induce phosphorylation of ATF4 through the action of RSK2 and PKA, respectively, to enhance ATF4’s transactivation ability in osteoblast.  Secondly, we would like to test whether phosphorylation of ATF4 induced by IGF1 or PTH accounts for cell-specificity via an increase in ATF4’s stability in osteoblasts.  Lastly, we will establish transgenic mice overexpressing ATF4-S251A and ATF4-S254A, two mutant forms of ATF4 that are no longer phosphorylated by RSK2 and PKA, specifically in osteoblasts to study the functional relevance of RSK2 and PKA phosphorylation of ATF4 in vivo.