The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis

Abstract

Mitogen-activated protein kinase pathways are implicated in the regulation of cell differentiation, although their precise roles in many differentiation programs remain elusive. The Raf/MEK/extracellular signal-regulated kinase (ERK) kinase cascade has been proposed to both promote and inhibit adipogenesis. Here, we titrate expression of the molecular scaffold kinase suppressor of Ras 1 (KSR1) to regulate signaling through the Raf/MEK/ERK/p90 ribosomal S6 kinase (RSK) kinase cascade and show how it determines adipogenic potential. Deletion of KSR1 prevents adipogenesis in vitro, which can be rescued by introduction of low levels of KSR1. Appropriate levels of KSR1 coordinate ERK and RSK activation with C/EBP␤ synthesis leading to the phosphorylation and stabilization of C/EBP␤ at the precise moment it is required within the adipogenic program. Elevated levels of KSR1 expression, previously shown to enhance cell proliferation, promote high, sustained ERK activation that phosphorylates and inhibits peroxisome proliferator-activated receptor gamma, inhibiting adipogenesis. Titration of KSR1 expression reveals how a molecular scaffold can modulate the intensity and duration of signaling emanating from a single pathway to dictate cell fate.

The Molecular Scaffold Kinase Suppressor of Ras 1 Is a Modifier of RasV12-Induced and Replicative Senescence

“…3 and 4) (37). However, ERK activation must be constrained within a narrow range by physiological levels of KSR1 to limit proliferative signals and promote adipogenesis (36,37). Therefore, KSR1 may be required to interact with MEK and moderate its activity when a biological effect requires restrained ERK activation (e.g., during differentiation).…”

“…Signaling through the Raf/ MEK/ERK cascade moderates cell fate decisions depending upon cellular context. Control of signal output through molecular scaffolds has been proposed as one of several nodes directing cell fate (35,36). In both primary and immortal MEFs, KSR1 expression moderates ERK activity to affect a cell fate ( Fig.…”

“…Kinase Suppressor of Ras 1 (KSR1) is a molecular scaffold for the Raf/MEK/ERK cascade (37,46,49). KSR1 expression regulates the intensity and duration of growth factor-induced ERK activation to modulate a cell's proliferative, oncogenic, and adipogenic potential (36,37,55). Importantly, immortalized KSR1…”

Kinase Suppressor of Ras 1 (KSR1) Regulates PGC1α and Estrogen-Related Receptor α To Promote Oncogenic Ras-Dependent Anchorage-Independent Growth

“…KSR2 Ϫ/Ϫ mice become spontaneously obese and possess cellular defects in both glucose uptake and fatty acid oxidation (13). KSR1 Ϫ/Ϫ mice have enlarged adipocytes and in vitro defects in adipogenesis and lipid accumulation (37). Because KSR proteins regulate both metabolism and tumorigenesis, we designed a study to determine how KSR1 impacts metabolism driven by oncogenic Ras.…”

Kinase Suppressor of Ras 2 (KSR2) Regulates Tumor Cell Transformation via AMPK

“…In C. elegans, KSR2 is required for Ras-mediated signaling during germ line meiotic progression and functions redundantly with KSR1 during development of the excretory system, hermaphrodite vulva, and male spicules (46). Subsequent studies in mammalian systems showed that KSR1 and KSR2 interact with Raf, MEK, and ERK to coordinate the intensity and duration of ERK signaling (3,9,10,29,31,54,62,63). Manipulation of KSR1 in mouse embryo fibroblasts (MEFs) revealed the intricate regulation of ERK signaling to enhance the oncogenic potential of Ras, adipogenic differentiation, and replicative senescence (29-31).…”