mTORC1 and mTORC2 Regulate EMT, Motility, and Metastasis of Colorectal Cancer via RhoA and Rac1 Signaling Pathways

Gulhati, Pat; Bowen, Kanika A.; Liu, Jianyu; Stevens, Payton D.; Rychahou, Piotr G.; Chen, Min; Lee, Eun Y.; Weiss, Heidi L.; O’Connor, Kathleen L.; Gao, Tianyan; Evers, B. Mark

doi:10.1158/0008-5472.can-10-4058

Cited by 496 publications

(417 citation statements)

References 22 publications

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“…Our results presented here strongly suggest that the defect in mTORC1 signaling resulting from dysregulation of the MID1/PP2A axis is one of the avenues leading to OS pathogenesis. Of note, malformations occurring in OS patients have been attributed to defective migration patterns of neural crest cells needed to mediate ventral midline tissue formation in a very specific time window during development (1), and mTORC1 signaling not only is responsible for cytoskeleton dynamics and intracellular transport-both processes that significantly influence the migration potential of cells-but also has a direct regulatory function in migrating cells (52,53). Dysfunctional mTORC1 signaling in OS patients with MID1 mutations is therefore likely to significantly contribute to the OS phenotype.…”

Section: Discussionmentioning

confidence: 99%

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Liu

Knutzen

Krauß

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of diverse ventral midline structures. The MID1 protein has been shown to function as an E3 ligase targeting the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitinmediated degradation. However, the molecular pathways downstream of the MID1/PP2A axis that are dysregulated in OS and that translate dysfunctional MID1 and elevated levels of PP2A-C into the OS phenotype are poorly understood. Here, we show that perturbations in MID1/PP2A affect mTORC1 signaling. Increased PP2A levels, resulting from proteasome inhibition or depletion of MID1, lead to disruption of the mTOR/Raptor complex and downregulated mTORC1 signaling. Congruously, cells derived from OS patients that carry MID1 mutations exhibit decreased mTORC1 formation, S6K1 phosphorylation, cell size, and cap-dependent translation, all of which is rescued by expression of wild-type MID1 or an activated mTOR allele. Our findings define mTORC1 signaling as a downstream pathway regulated by the MID1/PP2A axis, suggesting that mTORC1 plays a key role in OS pathogenesis.ubiquitin ligase | proteasome-mediated degradation M utations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of ventral midline structures. The clinical manifestations of Opitz syndrome are characterized by a diverse spectrum of symptoms, including hypertelorism and hypospadias, cleft lip/palate, dysphagia, heart defects, and mental retardation (1).The MID1 protein is a member of the RBCC/TRIM family, which contains a conserved module of the RING domain, followed by B-boxes and a coiled-coil domain (2). MID1 also contains fibronectin type III and B30.2/SPRY domains. The RING domain has been well characterized in ubiquitin-mediated protein degradation, whereas the other domains mediate proteinprotein interactions (3-6). Opitz syndrome-derived mutations in MID1 have been identified throughout the protein and show several functional consequences such as compromised association with microtubules and/or transport along microtubules (4, 7-9). In addition to its microtubule-binding function, MID1 also functions as an E3 ligase that targets the microtubule-associated pool of the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitin-mediated degradation through an interaction with the protein α4 (3). Perturbation of the E3 ligase function of MID1 in OS cells leads to the accumulation of PP2A-C and the dramatic dephosphorylation of microtubule-associated proteins, which is postulated to contribute to OS pathogenesis (3).Signaling from the mammalian target of rapamycin (mTOR) controls diverse cellular processes such as growth, autophagy, stress responses, cytoskeletal reorganization, cell motility, metabolism, and aging (10-12). mTORC1 consists of mTOR and the interacting proteins, Raptor, and mLST8. In particular, Raptor plays an essential scaffolding...

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Section: Discussionmentioning

confidence: 99%

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Liu

Knutzen

Krauß

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, we expected that the non-metastatic character of hamartomas from brain samples could be related to the hyperphosphorylation of CTNND-1 S268. Previous studies showed that elevated mTORC1 and mTORC2 activity played a role in regulating the epithelialmesenchymal transition (EMT), motility and metastasis of colorectal cancer (21). It has also been shown that CTNND1 P-S268 is an E-cadherin-associated protein that modulates E-cadherin function and stability (20).…”

Section: Discussionmentioning

confidence: 99%

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

et al. 2016

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Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR- specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.

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“…Activation of phosphatidylinositol 3-kinase (PI3K)/ Akt signaling through activating mutations in PI3KCA or loss of PTEN is associated with the progression of CRC (Roy et al, 2002). Gulhati et al (2011) have previously shown that the mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, could regulate the tumorigenesis of CRC. Their recent findings support a role for elevated mTORC1 and mTORC2 activity in regulating EMT and metastasis of CRC.…”

Section: Recently Demonstrated the Inhibitory Effect Roles Of Epithelmentioning

confidence: 99%

Epithelial-mesenchymal Transition and Its Role in the Pathogenesis of Colorectal Cancer

Zhu¹,

Gao²,

Wu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Epithelial-to-mesenchymal transition (EMT) is a collection of events that allows the conversion of adherent epithelial cells, tightly bound to each other within an organized tissue, into independent fibroblastic cells possessing migratory properties and the ability to invade the extracellular matrix. EMT contributes to the complex architecture of the embryo by permitting the progression of embryogenesis from a simple single-cell layer epithelium to a complex three-dimensional organism composed of both epithelial and mesenchymal cells. However, in most tissues EMT is a developmentally restricted process and fully differentiated epithelia typically maintain their epithelial phenotype. Recently, elements of EMT, specially the loss of epithelial markers and the gain of mesenchymal markers, have been observed in pathological states, including epithelial cancers. Increasing evidence has confirmed its presence in human colon during colorectal carcinogenesis. In general, chronic inflammation is considered to be one of the causes of many human cancers including colorectal cancer(CRC). Accordingly, epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel disease, have an increased risk of developing CRC. A large body of evidence supports roles for the SMAD/STAT3 signaling pathway, the NF-kB pathway, the Ras-mitogenactivated protein kinase/Snail/Slug and microRNAs in the development of colorectal cancers via epithelial-tomesenchymal transition. Thus, EMT appears to be closely involved in the pathogenesis of colorectal cancer, and analysis refered to it can yield novel targets for therapy.

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mTORC1 and mTORC2 Regulate EMT, Motility, and Metastasis of Colorectal Cancer via RhoA and Rac1 Signaling Pathways

Cited by 496 publications

References 22 publications

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

Epithelial-mesenchymal Transition and Its Role in the Pathogenesis of Colorectal Cancer

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