In vivo regulation of Yorkie phosphorylation and localization

Oh, Hyangyee; Irvine, Kenneth D.

doi:10.1242/dev.015255

Cited by 354 publications

(456 citation statements)

References 22 publications

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“…Activated Lats1/2 in turn phosphorylate YAP/TAZ transcription co-activators on several residues (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oka et al, 2008). Phosphorylation of S127 in YAP promotes 14-3-3 binding, resulting in cytoplasmic sequestration and therefore inactivation of YAP (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oh and Irvine, 2008). Indeed, mutation of S127 and disruption of 14-3-3 binding lead to activation of YAP (Zhao et al, 2007), confirming the inhibitory nature of this phosphorylation.…”

Section: The Mammalian Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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Section: The Mammalian Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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“…Many signaling pathways control these important cellular processes, including the recently described Salvador-Warts-Hippo (SWH) pathway, which includes several tumor suppressor genes, such as: fat (1,2) merlin (3), expanded, hippo (4), RASSF (5), Lats/Warts (6), Salvador (7) and an oncogene called yorkie (8)(9)(10) and controls cell growth, proliferation, and apoptosis (10). The ortholog of hSav1 in Drosophila, Salvador (SAV), has been reported as a core component of the SWH pathway.…”

Section: Introductionmentioning

confidence: 99%

hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells

Luo

Li²,

Li³

et al. 2011

Int J Mol Med

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Abstract. It has been reported that Salvador (SAV) is a core component of the Salvador-Warts-Hippo (SWH) pathway that restricts cell number, by functioning as a dual regulator of cell proliferation and apoptosis in Drosophila. However, the function of its human ortholog hSav1 (also called hWW45) in mammalian cells is poorly understood. In this study, we identified hematopoietic cell-specific protein 1 (HS1)-associated protein X-1 (HAX1), a 35-kda protein localized to cell mitochondria, as a novel binding partner of hSav1 using a yeast two-hybrid screening technique. Our finding was confirmed by immunoprecipitation and glutathione-S-transferase (GST) pull-down assays of both proteins. Using immunofluorescence staining, we showed that HAX1 and hSav1 interact with each other. Analysis of the anti-apoptotic function of HAX1 revealed that the presence of hSav1 attenuated the HAX1 protective effects from hydrogen peroxide (H 2 O 2 )-induced cell death in McF-7 cells, while knockdown of hSav1 by small interfering RNAs (siRNAs) significantly enhanced the anti-apoptotic function of HAX1. Also, using the Oncomine database, we found several studies in which HAX1 levels were significantly up-regulated and hSav1 expression was down-regulated in breast cancer samples compared to normal breast tissue. In summary, we conclude that hSav1 interacts with HAX1 and attenuates its protective role against apoptosis in McF-7 breast cancer cells.

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“…The activated Wts-Mats complex in turn phosphorylates the transcriptional coactivator Yorki (Yki) on S168 and creates a binding site for 14-3-3 proteins. Binding of 14-3-3 causes the cytoplasmic sequestration and inactivation of Yki (10)(11)(12)(13)(14). When the Hippo pathway is inactivated, Yki is dephosphorylated by an unknown phosphatase and translocates into the nucleus.…”

mentioning

confidence: 99%

Structural and functional analysis of the YAP-binding domain of human TEAD2

Tian¹,

Tomchick

et al. 2010

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

139

169

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The Hippo pathway controls organ size and suppresses tumorigenesis in metazoans by blocking cell proliferation and promoting apoptosis. The TEAD1-4 proteins (which contain a DNA-binding domain but lack an activation domain) interact with YAP (which lacks a DNA-binding domain but contains an activation domain) to form functional heterodimeric transcription factors that activate proliferative and prosurvival gene expression programs. The Hippo pathway inhibits the YAP-TEAD hybrid transcription factors by phosphorylating and promoting cytoplasmic retention of YAP. Here we report the crystal structure of the YAP-binding domain (YBD) of human TEAD2. TEAD2 YBD adopts an immunoglobulin-like β-sandwich fold with two extra helix-turn-helix inserts. NMR studies reveal that the TEAD-binding domain of YAP is natively unfolded and that TEAD binding causes localized conformational changes in YAP. In vitro binding and in vivo functional assays define an extensive conserved surface of TEAD2 YBD as the YAP-binding site. Therefore, our studies suggest that a short segment of YAP adopts an extended conformation and forms extensive contacts with a rigid surface of TEAD. Targeting a surface-exposed pocket of TEAD might be an effective strategy to disrupt the YAP-TEAD interaction and to reduce the oncogenic potential of YAP.Hippo pathway | oncogene | crystallography

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In vivo regulation of Yorkie phosphorylation and localization

Cited by 354 publications

References 22 publications

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells

Structural and functional analysis of the YAP-binding domain of human TEAD2

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