AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol

Jagannathan, Radhika; Schimizzi, Gregory V.; Zhang, Kun; Loza, Andrew J.; Yabuta, Norikazu; Nojima, Hitoshi; Longmore, Gregory D.

doi:10.1128/mcb.00136-16

Cited by 52 publications

(76 citation statements)

References 51 publications

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“…TRIP6-related LIM domain proteins have been shown to bind and inhibit LATS [9,[14][15][16]26,27]; however, it is not clear how they regulate LATS1/2 activity. Although Zyxin was shown to promote degradation of LATS1/2 in response to hypoxia [17], we did not observe any changes in LATS1 levels when TRIP6 levels were altered suggesting that TRIP6 uses a different mechanism. Because one of the TRIP6 binding sites in LATS2 (amino acids 625-644) overlaps with the binding site for its activator MOB1 (amino acids ▸ Figure 1.…”

Section: Trip6 Inhibits Lats1/2 By Blocking Binding To Mob1contrasting

confidence: 81%

“…The competition we observe between TRIP6 and MOB1 for binding to LATS1/2 is consistent with our other results showing TRIP6 interferes with MST1/2 phosphorylation of LATS1/2. This mechanism may be relevant for other LIM domain proteins that bind to a similar region of LATS1/2 (Abe et al [15]; Hirota et al [14]), and could function in conjunction with other proposed mechanisms for how LIM domain proteins inhibit LATS1/2 (Jagannathan et al [17]; Ma et al [18]; Sun et al [46]). ◀ Figure 3.…”

Section: Discussionmentioning

confidence: 95%

“…The mechanism by which Ajuba regulates Warts activity is not clearly understood. Although Zyxin and Ajuba LIM domain proteins have been shown to interact with LATS1/2 in mammalian cells [14][15][16], it is unclear whether Ajuba/Zyxin-related proteins function similarly in mammals [10,[17][18][19]. Here, we show that the human LIM domain protein TRIP6 acts as part of a mechanotransduction cascade at adherens junctions to regulate LATS1/2 in response to mechanical tension at cell-cell junctions.…”

Section: Introductionmentioning

confidence: 87%

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TRIP6 inhibits Hippo signaling in response to tension at adherens junctions

et al. 2017

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The transcriptional co-activator YAP controls cell proliferation, survival, and tissue regeneration in response to changes in the mechanical environment. It is not known how mechanical stimuli such as tension are sensed and how the signal is transduced to control YAP activity. Here, we show that the LIM domain protein TRIP6 acts as part of a mechanotransduction pathway at adherens junctions to promote YAP activity by inhibiting the LATS1/2 kinases. Previous studies showed that vinculin at adherens junctions becomes activated by mechanical tension. We show that vinculin inhibits Hippo signaling by recruiting TRIP6 to adherens junctions and stimulating its binding to and inhibition of LATS1/2 in response to tension. TRIP6 competes with MOB1 for binding to LATS1/2 thereby blocking MOB1 from recruiting the LATS1/2 activating kinases MST1/2. Together, these findings reveal a novel pathway that responds to tension at adherens junctions to control Hippo pathway signaling.

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Section: Trip6 Inhibits Lats1/2 By Blocking Binding To Mob1contrasting

confidence: 81%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 87%

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TRIP6 inhibits Hippo signaling in response to tension at adherens junctions

et al. 2017

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“…Basal LIMD1 gene expression is under the control of PU.1, a member of the Ets family of transcription factors (Foxler et al, 2011). LIMD1 can repress cell cycle progression through pRb-dependent and pRb-independent inhibition of E2F (Sharp et al, 2004) and regulates Hippo signalling by binding to LATS, causing sequestration of the Hippo kinase complex (Das Thakur et al, 2010;Codelia et al, 2014;Jagannathan et al, 2016). LIMD1 is also part of the Slug/Snail complex that regulates E-cadherin transcription (Ayyanathan et al, 2007;Langer et al, 2008) in addition to facilitating centrosomal localisation of BRCA2 to prevent aberrant cellular proliferation (Hou et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A HIF – LIMD 1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

et al. 2018

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The adaptive cellular response to low oxygen tensions is mediated by the hypoxia‐inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF‐α and HIF‐β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour‐suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF‐α subunit. Here, we identify LIMD1 as a HIF‐1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF‐α degradation by modulating PHD2‐LIMD1‐VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF‐α protein degradation, inhibiting HIF‐1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1‐negative lung cancers.

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“…Thus, members of this subfamily exhibit both shared and unique functions. For example, Ajuba proteins have been reported to participate in the regulation of Snail/Slug, microRNA-mediated gene silencing, and Hippo signaling pathways with similar functions (Jagannathan et al, 2016;James et al, 2010;Langer et al, 2008). LIMD1 and AJUBA have been reported to regulate cell cycle and proliferation, however, with contrary roles.…”

Section: Discussionmentioning

confidence: 99%

WT1‐interacting protein inhibits cell proliferation and tumorigenicity in non‐small‐cell lung cancer via the AKT/FOXO1 axis

Qiu

et al. 2019

Molecular Oncology

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Lung cancer is the most common cancer and the leading cause of cancer‐related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1‐interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non‐small‐cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression‐free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo ; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation‐related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.

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AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol

Cited by 52 publications

References 51 publications

TRIP6 inhibits Hippo signaling in response to tension at adherens junctions

TRIP6 inhibits Hippo signaling in response to tension at adherens junctions

A HIF – LIMD 1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

WT1‐interacting protein inhibits cell proliferation and tumorigenicity in non‐small‐cell lung cancer via the AKT/FOXO1 axis

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