A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration

Hervieu, Alexia; Heuss, Sara Farrah; Zhang, Chi; Barrow-McGee, Rachel; Joffre, Carine; Ménard, Ludovic; Clarke, Paul A.; Kermorgant, Stéphanie

doi:10.1126/scisignal.aba8627

Cited by 13 publications

(13 citation statements)

References 74 publications

(91 reference statements)

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“…Moreover, when analyzing Rac1 activity in an anchorage-independent growth (AIG) assay to mimic cell behavior in the absence of substrate adhesion, we observed activated Rac1 in suspension which we could readily inhibit using NSC 23766 after 4 h and 24 h of treatment, respectively (see Figures 3C and 3Di, average cluster size of 75 ± 4 mm; Figure S3E; Video S5). This is in line with Rac1 and other GTPases playing an active role in AIG and cancer cell survival in transit (Follain et al, 2020;Hervieu et al, 2020;Vennin et al, 2017). Interestingly, the outer versus inner cells of AIGs were further assessed, and while cells on the periphery of clusters were inherently more inactive than cells within the center of the cluster, they were also more readily inactivated by treatment with Rac1 inhibition than cells on the inside (Figure 3Dii).…”

Section: Rac1 Inhibition Enhances Vulnerability To Fluid-flowinduced Shear Stress and Results In Decreased Dissemination And Invasion Of supporting

confidence: 71%

Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging

et al. 2021

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Section: Rac1 Inhibition Enhances Vulnerability To Fluid-flowinduced Shear Stress and Results In Decreased Dissemination And Invasion Of supporting

confidence: 71%

Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging

et al. 2021

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“…TIPE2 can directly bind and inhibit Rac ( 39 ), which was confirmed in TIPE2-overexpressed NK92 cells (data not shown). Rac1 was previously shown to directly bind mTOR and mediate localization of mTORC1 and mTORC2 to specific membranes for their activation ( 50 ), and inhibition or deletion of Rac suppresses mTOR activity independently of PI3K ( 50 – 53 ). Therefore, TIPE2 might suppress mTOR activation by inhibiting Rac1.…”

Section: Discussionmentioning

confidence: 99%

TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity

Cheng

Zheng

et al. 2021

Sci. Adv.

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The maturation process of NK cells determines their functionality during which IL-15 plays a critical role. However, very few checkpoints specifically targeting this process have been discovered. Here, we report that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in both mice and humans. NK-specific TIPE2 deficiency increased mature NK cells in mice, and these TIPE2-deficient NK cells exhibited enhanced activation, cytotoxicity, and IFN- production upon stimulation and enhanced response to IL-15 for maturation. Moreover, TIPE2 suppressed IL-15-triggered mTOR activity in both human and murine NK cells. Consequently, blocking mTOR constrained the effect of TIPE2 deficiency on NK cell maturation in response to IL-15. Last, NK-specific TIPE2-deficient mice were resistant to tumor growth in vivo. Our results uncover a potent checkpoint in NK cell maturation and antitumor immunity in both mice and humans, suggesting a promising approach of targeting TIPE2 for NK cell-based immunotherapies.

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“…Some studies have shown that Rac1 can form a complex with mTOR to promote its transport to the plasma membrane (23).…”

Section: Rac1/cdc42 Can Regulate the Expression Of Mtormentioning

confidence: 99%

GEFT Inhibits Autophagy and Apoptosis in Rhabdomyosarcoma via Activation of the Rac1/Cdc42-mTOR Signaling Pathway

Song

et al. 2021

Front. Oncol.

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Autophagy and apoptosis are dynamic processes that determine the fate of cells, and regulating these processes can treat cancer. GEFT is highly expressed in rhabdomyosarcoma (RMS), which accelerates the tumorigenicity and metastasis of RMS by activating Rac1/Cdc42 signaling, but the regulatory mechanisms of autophagy and apoptosis are unclear. In our study, we found that the RMS tissues had high Rac1, Cdc42, mTOR, and Bcl-2 expression levels and low Beclin1, LC3, and Bax expression levels compared with the normal striated muscle tissues (P < 0.05). In addition, multivariate analysis has proven that Rac1 is an independent prognostic factor (P < 0.05), and the high expression level of the Beclin1 protein was closely associated with the tumor diameter of the RMS patients (P = 0.044), whereas the high expression level of the LC3 protein was associated with the clinical stage of the RMS patients (P = 0.027). Furthermore, GEFT overexpression could inhibit autophagy and apoptosis in RMS. A Rac1/Cdc42 inhibitor was added, and the inhibition of autophagy and apoptosis decreased. Rac1 and Cdc42 could regulate mTOR to inhibit autophagy and apoptosis in RMS. Overall, these studies demonstrated that the GEFT–Rac1/Cdc42–mTOR pathway can inhibit autophagy and apoptosis in RMS and provide evidence for innovative treatments.

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A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration

Cited by 13 publications

References 74 publications

Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging

Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging

TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity

GEFT Inhibits Autophagy and Apoptosis in Rhabdomyosarcoma via Activation of the Rac1/Cdc42-mTOR Signaling Pathway

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