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Regulation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling by wild-type and oncogenic Ras


Ras is a small GTPase that functions as a binary molecular switch, cycling between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. It is estimated that 30% of human tumors carry an oncogenic somatic mutation in one of three Ras isoforms. Oncogenic RAS alleles differ from their wild-type counterpart by a single missense point mutation that results in an amino acid substitution at position 12, 13, or 61. These amino acid substitutions impair the ability of GTPase activating proteins (GAPs) to facilitate GTP hydrolysis and consequently result in deregulated Ras signaling. Oncogenic Ras constitutively activates downstream effector pathways, including the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and promotes the uncontrolled growth, proliferation, and survival of cancer cells. In cancers for which there is no RAS mutation, increased signaling through the pathway is achieved by amplification or activation of upstream receptor tyrosine kinases, loss-of-function mutation in negative regulators, or activating mutation of downstream effectors, illustrating the importance of high pathway activity in the pathogenesis of cancer.

The oncogenic Ras isoform is thought to be primarily responsible for mediating the activation of downstream signaling pathways, although the two wild-type Ras isoforms remain functional. In fact, the signaling contribution of wild-type Ras in this context has largely been discounted and unexamined. The work presented here uncovers a novel role for wild-type Ras signaling in cancer cells with oncogenic RAS mutations. Wild-type Ras can be activated by external growth cues and inactivated by intrinsic regulatory proteins, and the modulation of wild-type Ras activity results in fluctuations in downstream signaling, despite the presence of oncogenic Ras. Additionally, this work demonstrates a critical role for wild-type Ras signaling in the proliferation of cancer cells expressing oncogenic RAS. These studies expand our understanding of the intricacies of Ras signaling and may uncover less obvious modes of targeting the pathway that have yet to be exploited.

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