Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

Abstract

Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation

“…S4 ). KSR2 is a molecular scaffold protein shown to be critical in the integration of various mitogenic and metabolic pathways 37 – 39 . As expected, we found SF3B1 regulated the KSR2 expression in endometrial cancer cells both at transcript and protein levels (Fig.…”

Regulators of the RAS-ERK pathway as therapeutic targets in thyroid cancer

“…The N-terminal CA1 domain contributes to BRAF and membrane binding, CA2 is a proline-rich domain with no described function, CA3 is a cysteine-rich domain that mediates membrane binding and CA4 presents a motif for interaction with ERK. Finally, the CA5 region includes a putative kinaselike domain, although it is still unclear whether it actually displays kinase activity (Frodyma et al 2017). Single knockout mice Ksr1 and Ksr2 show different phenotypes, indicating that the proteins fulfill independent functions (Lozano et al 2003, Costanzo-Garvey et al 2009).…”

Genetics of Severe Obesity

“… Han et al 2016 [ 11 ] KSR2 Kinase suppressor of ras 2 12q24.22-q24.23 Severe Hyperphagia (in childhood), insulin resistance and reduced basal metabolic rate. Frodyma et al 2017 [ 12 ] LEP Leptin 7q32.1 Severe, early onset Hyperphagia, hypogonadotropic hypogonadism. Some evidence for neuroendocrine/metabolic and immune dysfunction Wasim et al 2016; Yeo 2017 [ 13 , 14 ] LEPR Leptin receptor 1p31.3 Severe, early onset Hyperphagia, hypogonadotropic hypogonadism.…”