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A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas.

Deel MD, Li JJ, Crose LE, Linardic CM - Front Oncol (2015)

Bottom Line: For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes.Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype.This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Pediatrics, Duke University School of Medicine , Durham, NC , USA.

ABSTRACT
The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the mammalian Hippo signaling cascade. Canonical Hippo transduction involves MST1/2 and LATS1/2 kinases, which, in conjunction with SAV1 and MOB1, phosphorylate, and inhibit the transcriptional co-activators YAP and TAZ. Regulation of YAP and TAZ are governed by plasma membrane proteins, cytoskeletal adaptor proteins, regulatory cross-talk from other signaling pathways, and intrinsic and extrinsic mechanical cues with the actin cytoskeleton. For simplicity, not all the known protein–protein interactions and regulators of Hippo signaling are represented. When Hippo signaling is “OFF”, YAP/TAZ translocate to the nucleus to serve as transcriptional co-activators for TEADs as well as other transcription factors (only a few of which are represented here) involved in cellular proliferation, differentiation, self-renewal, and apoptosis. See text for additional details.
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Figure 1: Schematic representation of the mammalian Hippo signaling cascade. Canonical Hippo transduction involves MST1/2 and LATS1/2 kinases, which, in conjunction with SAV1 and MOB1, phosphorylate, and inhibit the transcriptional co-activators YAP and TAZ. Regulation of YAP and TAZ are governed by plasma membrane proteins, cytoskeletal adaptor proteins, regulatory cross-talk from other signaling pathways, and intrinsic and extrinsic mechanical cues with the actin cytoskeleton. For simplicity, not all the known protein–protein interactions and regulators of Hippo signaling are represented. When Hippo signaling is “OFF”, YAP/TAZ translocate to the nucleus to serve as transcriptional co-activators for TEADs as well as other transcription factors (only a few of which are represented here) involved in cellular proliferation, differentiation, self-renewal, and apoptosis. See text for additional details.

Mentions: As shown in Figure 1, the mammalian Hippo pathway relays plasma membrane and cytoplasmic signals into the nucleus, where it regulates the expression of a diverse group of target genes that control essential cellular processes, including proliferation, differentiation, and apoptosis. Canonical Hippo transduction involves serine/threonine kinases mammalian STE20-like protein kinase 1/2 (MST1/2, which are homologs of Drosophila Hippo) (4, 5, 11, 12) and large tumor suppressor homolog 1/2 (LATS1/2) (7, 13, 14), which, in conjunction with adaptor proteins Salvador homolog 1 (SAV1) (12) and Mob kinase activator 1 (MOB1) (15), phosphorylate and inhibit the transcriptional co-activators Yes-associated protein 1 (YAP, a homolog of Yorkie) and transcriptional co-activator with PDZ-binding motif (TAZ) [also known as WW domain-containing transcription regulator 1, WWTR1] (16). The Hippo pathway is “ON” when MST1/2 and LATS1/2 kinases are active. Through an interaction between the PPxY (PY) motifs of LATS1/2 and the WW domains of YAP and TAZ, activated LATS1/2 lead to phosphorylation of YAP and TAZ, which results in YAP/TAZ cytoplasmic retention and β-TRCP (β-transducin repeat-containing E3 ubiquitin protein ligase)-dependent proteasomal degradation (9, 10). When Hippo signaling is inactive or “OFF”, YAP and TAZ are localized to the nucleus, where they serve as transcriptional co-activators for TEA domain-containing sequence-specific transcription factors (TEADs) (17–21) as well as other transcription factors (16).


A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas.

Deel MD, Li JJ, Crose LE, Linardic CM - Front Oncol (2015)

Schematic representation of the mammalian Hippo signaling cascade. Canonical Hippo transduction involves MST1/2 and LATS1/2 kinases, which, in conjunction with SAV1 and MOB1, phosphorylate, and inhibit the transcriptional co-activators YAP and TAZ. Regulation of YAP and TAZ are governed by plasma membrane proteins, cytoskeletal adaptor proteins, regulatory cross-talk from other signaling pathways, and intrinsic and extrinsic mechanical cues with the actin cytoskeleton. For simplicity, not all the known protein–protein interactions and regulators of Hippo signaling are represented. When Hippo signaling is “OFF”, YAP/TAZ translocate to the nucleus to serve as transcriptional co-activators for TEADs as well as other transcription factors (only a few of which are represented here) involved in cellular proliferation, differentiation, self-renewal, and apoptosis. See text for additional details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557106&req=5

Figure 1: Schematic representation of the mammalian Hippo signaling cascade. Canonical Hippo transduction involves MST1/2 and LATS1/2 kinases, which, in conjunction with SAV1 and MOB1, phosphorylate, and inhibit the transcriptional co-activators YAP and TAZ. Regulation of YAP and TAZ are governed by plasma membrane proteins, cytoskeletal adaptor proteins, regulatory cross-talk from other signaling pathways, and intrinsic and extrinsic mechanical cues with the actin cytoskeleton. For simplicity, not all the known protein–protein interactions and regulators of Hippo signaling are represented. When Hippo signaling is “OFF”, YAP/TAZ translocate to the nucleus to serve as transcriptional co-activators for TEADs as well as other transcription factors (only a few of which are represented here) involved in cellular proliferation, differentiation, self-renewal, and apoptosis. See text for additional details.
Mentions: As shown in Figure 1, the mammalian Hippo pathway relays plasma membrane and cytoplasmic signals into the nucleus, where it regulates the expression of a diverse group of target genes that control essential cellular processes, including proliferation, differentiation, and apoptosis. Canonical Hippo transduction involves serine/threonine kinases mammalian STE20-like protein kinase 1/2 (MST1/2, which are homologs of Drosophila Hippo) (4, 5, 11, 12) and large tumor suppressor homolog 1/2 (LATS1/2) (7, 13, 14), which, in conjunction with adaptor proteins Salvador homolog 1 (SAV1) (12) and Mob kinase activator 1 (MOB1) (15), phosphorylate and inhibit the transcriptional co-activators Yes-associated protein 1 (YAP, a homolog of Yorkie) and transcriptional co-activator with PDZ-binding motif (TAZ) [also known as WW domain-containing transcription regulator 1, WWTR1] (16). The Hippo pathway is “ON” when MST1/2 and LATS1/2 kinases are active. Through an interaction between the PPxY (PY) motifs of LATS1/2 and the WW domains of YAP and TAZ, activated LATS1/2 lead to phosphorylation of YAP and TAZ, which results in YAP/TAZ cytoplasmic retention and β-TRCP (β-transducin repeat-containing E3 ubiquitin protein ligase)-dependent proteasomal degradation (9, 10). When Hippo signaling is inactive or “OFF”, YAP and TAZ are localized to the nucleus, where they serve as transcriptional co-activators for TEA domain-containing sequence-specific transcription factors (TEADs) (17–21) as well as other transcription factors (16).

Bottom Line: For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes.Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype.This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Pediatrics, Duke University School of Medicine , Durham, NC , USA.

ABSTRACT
The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

No MeSH data available.


Related in: MedlinePlus