Kinase suppressor of Ras 2 (KSR2)

Kinase suppressor of Ras 2 (KSR2) is a scaffolding protein that coordinates Ras-dependent MAPK pathway signal transmission by assembling the Raf, MEK, and ERK kinases into multicomponent complexes, thereby facilitating efficient signaling. Unlike its paralog KSR1, KSR2 plays critical roles in regulating energy expenditure, nutrient metabolism, and AMPK signaling, with its loss in mice resulting in obesity, insulin resistance, and infertility. KSR2 can enhance cell proliferation and tumor cell anchorage-independent growth, acting synergistically with oncogenic Ras, and is fundamental for maximal glycolytic and oxidative phosphorylation capacity in cancer cells. It is predicted to act as a low-activity kinase (phosphorylates MEK1 on noncanonical sites) and as an allosteric activator of BRAF in the MAPK pathway. Human genetic KSR2 variants are implicated in severe early-onset obesity and metabolic disorders. Currently, KSR2 is not a direct drug target, but is under active investigation for its role in cancer and metabolic syndromes.

Other names

KSR2hKSR2FLJ25965kinase suppressor of ras 2

Not directly targeted by drugs, but known mechanisms of regulation include: Allosteric activation of BRAF upon binding to MEK1/2, promoting BRAF-mediated MEK phosphorylation; Scaffolding of Raf/MEK/ERK signaling complexes to regulate downstream MAPK pathway activation; Activation and regulation of AMPK signaling for metabolic effects.