TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

Fleming, Yvonne; Ferguson, Gail; Spender, Lindsay C.; Larsson, Jonas; Karlsson, Stefán; Ozanne, Brad; Grosse, Robert; Inman, Gareth J.

doi:10.1038/onc.2008.449

Cited by 44 publications

(49 citation statements)

References 31 publications

(59 reference statements)

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“…We tested the hypothesis that TGF-β to ROCK signaling requires ALK5 activity in the context of mTORC1 loss of function, a finding that has been documented in other contexts (84). ALK5 inhibition or knockdown inhibited stress fiber formation and improved cortical organization of actin and phosphorylated MLC2.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Asrani¹,

Sood²,

Torres³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Asrani¹,

Sood²,

Torres³

et al. 2017

Journal of Clinical Investigation

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“…These observations suggest that the contributions of Akt1 and Akt2 might vary, depending on the cell system and EMT inducer. TGF-b is known to activate RhoA in a manner that is dependent upon the TbRI kinase (Fleming et al, 2009), and its downstream kinase p160 ROCK in epithelial cells, and their activities are required for EMT (Bhowmick et al, 2001). How TbRI mechanistically links to RhoA was unclear.…”

Section: Role Of Mtorc2 In Tgf-b Signalingmentioning

confidence: 99%

TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion

Lamouille

Connolly

Smyth

et al. 2012

Journal of Cell Science

264

196

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SummaryIn cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition of mesenchymal properties, a process that can lead to epithelial-mesenchymal transition (EMT). TGF-b is a potent inducer of EMT, and increased TGF-b signaling in cancer cells is thought to drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) in cells undergoing EMT. TGF-b rapidly induces mTORC2 kinase activity in cells undergoing EMT, and controls epithelial cell progression through EMT. By regulating EMT-associated cytoskeletal changes and gene expression, mTORC2 is required for cell migration and invasion. Furthermore, inactivation of mTORC2 prevents cancer cell dissemination in vivo. Our results suggest that the mTORC2 pathway is an essential downstream branch of TGF-b signaling, and represents a responsive target to inhibit EMT and prevent cancer cell invasion and metastasis.

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“…During metastasis, tumour cells may switch between these modes of invasion depending on the activation status of specific Rho GTPases (Sanz-Moreno et al, 2008). Hence, alterations of Rho GTPase signalling is found in many tumours and can contribute to progression and metastasis by influencing growth, oncogenic transformation, survival and cell motility (Fleming et al, 2009;Karlsson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC

et al. 2010

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Invasive cell migration is a key step for cancer metastasis and involves Rho GTPase-controlled reorganization of the actin cytoskeleton. Altered Rho GTPase expression is found in various malignancies. Particularly, the closely related GTPases RhoA and RhoC are upregulated in many aggressive tumours, but specific effectors that distinguish between these two GTPases to explain mechanistic differences have not been identified. The formins are by far the largest family of Rho GTPase effectors and are characterized by the actin-nucleating formin homology 2 domain. Using siRNA-based screening against all 15 human formins, we systematically analysed their functions in 3D cell motility using three different cancer cell lines. These results reveal distinct requirements for specific formins in amoeboid versus mesenchymal invasive cell migration. Importantly, by knocking down all Rho proteins, we identified formin-like 2 (FMNL2) as a specific RhoC effector, showing selective interaction of FMNL2 with active RhoC, but not RhoA or RhoB. Functional analysis shows that RhoC regulates autoinhibition of FMNL2, whereas suppression of FMNL2 inhibits RhoC-, but not RhoA-dependent, rounded invasive cell migration. Thus, our data uncover a novel regulatory and functional interaction between RhoC and FMNL2 for modulating cell shape and invasiveness and provide mechanistic insight into RhoC-specific signalling events.

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TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

Cited by 44 publications

References 31 publications

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion

Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC

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