Rictor regulates cell migration by suppressing RhoGDI2

Agarwal, Nitin; Chen, Chien‐Hung; Cho, Hyojin; Boulbès, Delphine R.; Spooner, Eric; Sarbassov, Dos D.

doi:10.1038/onc.2012.287

Cited by 59 publications

(65 citation statements)

References 32 publications

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“…Of interest, our data show that WSB1 selectively inhibits RhoGDI2 but not RhoGDI1. Although it remains to be determined how WSB1 carries out this distinctive regulation, a similar phenomenon has also been observed in rictor-triggered RhoGDI2 expression, as revealed by the increase in RhoGDI2 rather than RhoGDI1 in rictor-null MEFs (41,42). Because only the loss of RhoGDI2, but not RhoGDI1, has been reported to be associated with metastasis, and because the functional distinction between RhoGDI1 and RhoGDI2 remains elusive, these clues further suggest the existence of highly organized intracellular network that coordinates individual signaling to mediate metastasis.…”

Section: Discussionmentioning

confidence: 77%

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

et al. 2015

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Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. Cancer Res; 75(22); 4839-51. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 77%

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

et al. 2015

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“…mTORC2-dependent activation of protein kinase C (PKC)-␣, paxillin (an actin filament regulatory protein), and Rho GTPases, among others, affects the actin cytoskeleton dynamics and regulates cell shape (3,191,357).…”

Section: Mtor Sirtuins and Klotho: The Most Consistently Altered Tamentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…We subsequently validated the microarray results by qRT-PCR of several genes, ADCY7, ARGHDIB, BAMBI, FOXG1, FSCN1, FUCA1, GFPT2, ITPR3, ITGA4, LSP1, NCAM1, NUDT14, RGS20, RHOF, and RIAM, that have already been implicated in cell migration, adhesion, or angiogenesis (28,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). The results from qRT-PCR analysis (Fig.…”

Section: Differential Gene Expression Analysis Of Pr9692shmock and Prmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

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Rictor regulates cell migration by suppressing RhoGDI2

Cited by 59 publications

References 32 publications

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

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