Molecular interpretation of ERK signal duration by immediate early gene products

Abstract

A molecule with a sense of timing uration of kinase signaling determines how a cell responds to external cues like growth factors. But how a cell measures signaling time has been a mystery. Now, Leon Murphy, John Blenis (Harvard Medical School, Boston, MA), and colleagues have found that immediate early gene (IEG) products have a sensor mechanism that makes these distinctions. Their findings may provide a target for cancer treatment drugs. Growth factors PDGF and EGF elicit different responses in fibroblasts, with only PDGF inducing cells to enter S-phase. The group found that EGF transiently activated ERK MAP kinases, whereas PDGF stimulated prolonged activation. The IEG product c-Fos is known to be transcribed with similar ki-netics in response to either growth factor , but c-Fos was only phosphorylated when ERK activity was sustained. This not only stabilized c-Fos, but also primed it for further phosphorylation by revealing a DEF domain, an ERK-docking motif. Without secondary phos-phorylation, c-Fos was less able to promote cellular transformation. "Since several other IEGs also have DEF domains," says Blenis, "this group of IEGs may act as molecular sensors in many processes," including neuronal differentiation and the generation of an immune response. Blenis and Murphy hope it will be possible to antagonize these sensors to block specifically ERK-regulated proliferation, such as that seen in Ras-induced cancers, thus possibly avoiding toxic side effects caused by disturbing ERK's other homeostatic cellular functions.

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Cell fates determined by these MAPK components also differ depending on the strength and duration of signaling. For example, in some systems the platelet-derived growth factor (PDGF) stimulates sustained ERK activity and results in S-phase entry or cell differentiation whereas epidermal growth factor (EGF) stimulates transient ERK activity that does not drive cells in to S-phase and does not promote cell differentiation [204][205][206][207]. Duration and strength dependent modulation of cell fate appear to operate in neuronal PC12 cells, NIH3T3 fibroblasts [208], macrophages [209] and lymphocytes [210,211].…”

Computational approaches for modeling regulatory cellular networks

“…In the neuronal cell line PC12, short duration of MAPK-1,2 signaling is thought to promote proliferation, whereas sustained MAPK-1,2 signaling is thought to promote differentiation [50][51][52]. Recent studies by Murphy and co-workers have elucidated a feed-forward mechanism that decodes the duration of MAPK activation in terms of IEGs expression and function [53,54].…”

“…Fos and several other MAPK1,2-responsive IEGs contain a DEF domain that binds to MAPK1,2 [53,54,56]. Thus, part of the capability to induce feed-forward regulation and time bridges is `hard wired' into the components of the pathway, enabling the cell to decode the duration and amplitude of the external signal.…”

“…Feed-forward relay for decoding signal duration. Recent studies by Blenis and co-workers have elucidated a potential mechanism for decoding the duration of a mitogen-activated protein kinase (MAPK) response [53,54]. The decoder essentially works as a feed-forward relay system.…”

Epi-allelic Erk1 and Erk2 knockdown series for quantitative analysis of T cell Erk regulation and IL-2 production

“…A mathematical modeling effort has demonstrated how the balance between this novel Erk positive feedback and negative feedback via phosphatase-mediated deactivation of molecules proximal to the TCR allows for sensitivity in ligand discrimination (8). A downstream positive feedback loop between Erk-mediated immediate early gene (9) expression and Erk has also been described (10). The dynamic integration of multiple feedbacks both upstream and downstream may yield a strong dependence of T cell responses to Erk activity.…”