The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2

Kovalski, Joanna; Bhaduri, Aparna; Zehnder, Ashley; Neela, Poornima H.; Che, Yonglu; Wozniak, Glenn G.; Khavari, Paul A.

doi:10.1016/j.molcel.2018.12.001

Cited by 112 publications

(147 citation statements)

References 60 publications

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“…Similarly, we did not find evidence of Ras pathwayassociated proteins or GTPases in our proximal biotin labeling experiments. These findings are consistent with Ras-centric proteomic studies that have not identified RASSF proteins as endogenous interactors of either wild type or mutant Ras proteins 51 . Instead, we here define the RASSF2-proximal proteome in leukemia cells and demonstrate the critical importance of its endogenous interaction with Hippo kinases, MST1 and MST2, through the C-terminal SARAH domain.…”

Section: Discussionsupporting

confidence: 89%

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling

et al. 2020

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Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.

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Section: Discussionsupporting

confidence: 89%

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling

et al. 2020

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“…This suggests that either Hras Q61L is not as oncogenic as Kras Q61L or the encoded protein is expressed too low (or high) to be tumorigenic. In support of the first, RAS isoforms differ in their residency at different membranes 50 and the composition of proteins within the immediate vicinity differs between RAS isoforms 51,52 , with proteins like PIP5K1A 52 , calmodulin 53 , galectin-3 54 , and so forth documented to specifically associate with KRAS. In support of the second, a Kras allele whereby the 3ʹ end was replaced with Hras exons to encode Hras protein was found mutated in urethane-induced tumors 55 , indicating that under a Kras promoter Hras Q61L is indeed oncogenic in the lung.…”

Section: Discussionmentioning

confidence: 94%

Capturing the primordial Kras mutation initiating urethane carcinogenesis

MacAlpine

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2020

Nat Commun

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The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q 61 L/R mutation in the gene Kras. Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to human cancers. To elucidate the principles underlying this RAS mutation tropism of urethane, we adapted an error-corrected, high-throughput sequencing approach to detect mutations in murine Ras genes at great sensitivity. This analysis not only captured the initiating Kras mutation days after urethane exposure, but revealed that the sequence specificity of urethane mutagenesis, coupled with transcription and isoform locus, to be major influences on the extreme tropism of this carcinogen.

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“…Another interesting finding is that the positively charged amino acid cluster KKGK motif at the juxtamembrane region of CD146 is essential for CD146-mediated mTORC2 activation by GFs, although direct visualization of the PM-associated CD146-Rictor is not applicable, because of unavailability of suitable antibodies. Recently, it has been identified that oncogenic active Ras binds and stimulates mTORC2 (Kovalski et al, 2019). Given that all Ras proteins contain similar positively charged amino acid clusters in their hypervariable region, which is in a close vicinity to the PM anchor site (Simanshu et al, 2017), it is plausible that oncogenic Ras stimulates mTORC2 by binding to Rictor through these clusters.…”

Section: Discussionmentioning

confidence: 99%