RAS Proteins and Their Regulators in Human Disease

Abstract

RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

“…KRAS is one of the most frequently mutated oncogenes in cancer42 but is only rarely mutated in HCC 14. Therefore, the expression and function of KRAS in HCC were widely unexplored.…”

KRAS Alleles: The Devil Is in the Detail

“…The Rat sarcoma ( RAS ) oncogene family is comprised of three members ( KRAS , HRAS , and NRAS ) that play an important role in human cancer [1]. All RAS genes encode 21 kD monomeric GTPases that function to transduce extracellular signals to intracellular signal transduction cascades.…”

“…Missense mutations in RAS proteins alter the homeostatic balance of GDP and GTP binding toward the active state, either by reducing GTP hydrolysis or by increasing the rate of GTP loading. There has been considerable work over the past several decades comparing mutant and wild-type (WT) forms of RAS [1, 2], with relatively little attention paid to potential differences between the specific mutations that give rise to the activated oncoproteins. This review explores the broad array of evidence for functionally distinct allelic forms of RAS.…”

Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

“…This hypothesis is particularly attractive in view of the frequency of RAS gene mutations in human cancers and the difficulties of targeting mutant RAS proteins [47][48][49] . Because DUSP6 directly controls the activities of ERK1…”