Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)

Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2008; 283(41):27534-46. DOI: 10.1074/jbc.M804380200
Source: PubMed


The Hippo pathway in Drosophila controls the size and shape of organs. In the fly, activation of this pathway conveys growth-inhibitory signals and promotes apoptosis in epithelial cells. We "reconstituted" the Hippo pathway in a human epithelial cell line and showed that, in contrast to flies, the activation of this pathway results in anti-apoptotic signals. We have shown that in human embryonic kidney (HEK) 293 cells, the complex formation between transcriptional co-activators YAPs (Yes kinase-associated proteins) and Lats kinases requires the intact WW domains of YAPs, as well as intact Pro-Pro-AA-Tyr (where AA is any amino acid) motifs in Lats kinases. These kinases cooperate with the upstream Mst2 kinase to phosphorylate YAPs at Ser-127. Overexpression of YAP2 in HEK293 cells promoted apoptosis, whereas the Mst2/Lats1-induced phosphorylation of YAP partially rescued the cells from apoptotic death. Apoptotic signaling of YAP2 was mediated via stabilization of p73, which formed a complex with YAP2. All components of the Hippo pathway that we studied were localized in the cytoplasm, with the exception of YAP, which also localized in the nucleus. The localization of YAP2 in the nucleus was negatively controlled by the Lats1 kinase. Our apoptotic "readout" of the Hippo pathway in embryonic kidney cells represents a useful experimental system for the identification of the putative upstream receptor, membrane protein, or extracellular factor that initiates an entire signaling cascade and ultimately controls the size of organs.

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    • "Phosphorylated YAP and TAZ bind to 14-3-3, which sequesters YAP/TAZ in the cytoplasm where they are subsequently proteasomally degraded (Hong and Guan 2012). YAP/ TAZ can also be sequestered at both tight and adherens junctions through direct binding to proteins that localize there (Avruch et al. 2012; Bertini et al. 2009; Zhao et al. 2010b, 2011; Oka et al. 2008). Ultimately, activation of the Hippo pathway prevents YAP and TAZ from entering the nucleus and activating the transcriptional enhancer activation domain (TEAD)-family of transcription factors to initiate the expression of genes important for cell growth and survival (Pan 2010; Yu and Guan 2013; Zhao et al. 2010a, b, 2011). "
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    ABSTRACT: Centrosome amplification is a common feature of both solid and hematological human malignancies. Extra centrosomes are not merely innocent bystanders in cancer cells, but rather promote tumor progression by disrupting normal cellular architecture and generating chromosome instability. Consequently, centrosome amplification correlates with advanced tumor grade and overall poor clinical prognosis. By contrast, extra centrosomes are adversely tolerated in non-transformed cells and hinder cell proliferation. This suggests that in addition to acquiring extra centrosomes, cancer cells must also adapt to overcome the deleterious consequences associated with them. Here, we review evidence that implicates core components of the Hippo tumor suppressor pathway as having key roles in both the direct and indirect regulation of centrosome number. Intriguingly, functional inactivation of the Hippo pathway, which is common across broad spectrum of human cancers, likely represents one key adaptation that enables cancer cells to tolerate extra centrosomes.
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    • "The YAP serine 127 to alanine (S127A) mutant is a constitutively active form that remains in the nucleus and is transcriptionally active. YAP regulates the balance between cell proliferation and apoptosis [18], [19], [20], and is amplified in a number of human malignancies including breast, esophageal, hepatocellular, ependymoma, malignant mesothelioma and medulloblastoma [21], [22], [23], [24], [25], [26]. In addition, YAP expression correlates with poor prognosis in various cancers, such as colorectal, esophageal, gastric, hepatocellular, lung and ovarian [22], [27], [28], [29], [30], [31], [32], "
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    • "YAP1 has several domains containing a TEAD binding region and 2 WW domains, which are DNA binding domains that function as transcriptional coactivators through interactions with DNA binding transcription factors [51], [52], [53]. YAP1 can transactivate growth-promoting genes and enhance p73-dependent apoptosis in response to DNA damage by binding to specific domains [54], [55], [56]. Here, for the first time, we show that YAP1 is a direct target of gga-miR-375. "
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