Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase

TLDR

Growth factors activate CREB by phosphorylating it at serine‑133 through the RAS‑MAPK pathway. RSK2, a pp90(RSK) family kinase, is the CREB kinase that mediates growth‑factor–induced phosphorylation of CREB in vitro and in vivo. These results establish RSK2 as the mediator that transduces RAS‑MAPK signals to CREB, linking extracellular growth‑factor stimulation to nuclear gene activation.

Abstract

A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression.