Frequent epigenetic inactivation of<i>KIBRA,</i>an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia

Hill, Victoria; Dunwell, Thomas L.; Catchpoole, Daniel; Krex, Dietmar; Brini, A.T.; Griffiths, Mike; Craddock, Charles; Maher, Eamonn R.; Latif, Farida

doi:10.4161/epi.6.3.14404

Cited by 45 publications

(56 citation statements)

References 37 publications

(43 reference statements)

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“…Overexpression of YAP in a conditional YAP transgenic mouse model led to tissue overgrowth and tumorigenesis (40). Furthermore, mutation or epigenetic silencing of several components of the Hippo pathway, including NF2, LATS1/2, MST1/2, WW45, MOB, and KIBRA, have been associated with several human cancers (30,35,41). Together, these studies highlight a pivotal role of the Hippo-YAP pathway in cancer development and progression, but the transcriptional targets remain unclear.…”

Section: Significancementioning

confidence: 95%

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

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

277

284

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Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.

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Section: Significancementioning

confidence: 95%

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Wang

et al. 2013

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

277

284

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“…It was also reported to interact with discoidin domain receptor 1 to modulate collageninduced signaling (34). Interestingly, KIBRA expression was suppressed by promoter methylation in B-cell acute lymphocytic leukemia (35), suggesting a potential tumor suppressive function, as it was in Drosophila (36 -38). We recently reported that in mammalian cells KIBRA regulates the Hippo-YAP signaling activity via interactions with Lats1/2 kinases and demonstrated that KIBRA is also a transcriptional target induced by YAP (39).…”

mentioning

confidence: 99%

KIBRA Protein Phosphorylation Is Regulated by Mitotic Kinase Aurora and Protein Phosphatase 1

Xiao¹,

Chen²,

et al. 2011

Journal of Biological Chemistry

113

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Recent genetic studies in Drosophila identified Kibra as a novel regulator of the Hippo pathway, which controls tissue growth and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. The cellular function and regulation of human KIBRA remain largely unclear. Here, we show that KIBRA is a phosphoprotein and that phosphorylation of KIBRA is regulated in a cell cycle-dependent manner with the highest level of phosphorylated KIBRA detected in mitosis. We further demonstrate that the mitotic kinases Aurora-A and -B phosphorylate KIBRA both in vitro and in vivo. We identified the highly conserved Ser 539 as the primary phosphorylation site for Aurora kinases. Moreover, we found that wild-type, but not catalytically inactive, protein phosphatase 1 (PP1) associates with KIBRA. PP1 dephosphorylated Aurora-phosphorylated KIBRA. KIBRA depletion impaired the interaction between Aurora-A and PP1. We also show that KIBRA associates with neurofibromatosis type 2/Merlin in a Ser 539 phosphorylation-dependent manner. Phosphorylation of KIBRA on Ser 539 plays a role in mitotic progression. Our results suggest that KIBRA is a physiological substrate of Aurora kinases and reveal a new avenue between KIBRA/Hippo signaling and the mitotic machinery.The Hippo signaling pathway, originally defined in Drosophila, controls organ size, tumorigenesis, and cell contact inhibition by regulating cell proliferation and apoptosis (1-3). In mammalian cells, kinases Mst1/2 (orthologs of Drosophila Hippo) phosphorylate and activate Lats1/2 (orthologs of Warts) (4, 5). Lats, in turn, phosphorylates and inactivates the downstream effectors YAP/TAZ (orthologs of Yorkie) (6 -9). The transcriptional coactivators YAP and TAZ function together with transcription factors such as TEAD1-4 (Scalloped in Drosophila) (10 -13) to induce target gene expression, including Birc5 (8), cytokines such as connective tissue growth factor (10,14), and the EGF family member amphiregulin (15). Accumulated evidence suggests that this emerging signaling pathway plays a critical role in cancer development with the most evident contribution to hepatocellular carcinoma (1, 2, 16). For example, mice lacking Lats1 or WW45 (ortholog of Salvador) develop several types of tumors (17)(18)(19). Overexpression of YAP or loss of Mst1 and Mst2 in mouse liver dramatically increases the organ size and eventually induces hepatocellular carcinoma (8, 20 -23). The YAP locus is consistently amplified, and elevated YAP expression has been observed in many human cancers, including liver cancers (8, 14, 24 -26).KIBRA, a WW domain-containing protein (27), was originally identified as a memory performance-associated protein (28 -30). The physiological function of human KIBRA is not well understood, although it has been shown to play a role in podocyte migration (31, 32) and to be involved in age-dependent risk of Alzheimer disease (33). It was also reported to interact with discoidin domain receptor 1 to modulate collageninduced signaling (34). Interestingly, KIBRA expression wa...

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“…KIBRA also interacts with the motor protein dynein light chain 1 to positively regulate cell growth in breast cancer cells (37). Interestingly, KIBRA expression is frequently down-regulated by promoter methylation in B-cell acute lymphocytic leukemia (38) and chronic lymphocytic leukemia (39) but not in epithelial cancers, including breast, colorectal, kidney, lung, and prostate, suggesting a potential cell type-specific tumor suppressive function of KIBRA. However, a role of KIBRA in cancer (including leukemia) development has not been established.…”

mentioning

confidence: 99%

KIBRA Regulates Aurora Kinase Activity and Is Required for Precise Chromosome Alignment During Mitosis

Zhang¹,

Iyer²,

Chowdhury³

et al. 2012

Journal of Biological Chemistry

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Frequent epigenetic inactivation ofKIBRA,an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia

Cited by 45 publications

References 37 publications

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

KIBRA Protein Phosphorylation Is Regulated by Mitotic Kinase Aurora and Protein Phosphatase 1

KIBRA Regulates Aurora Kinase Activity and Is Required for Precise Chromosome Alignment During Mitosis

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