Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

Zheng, Yonggang; Liu, Bo; Wang, Li; Lei, Huiyan; Prieto, Katiuska Daniela Pulgar; Pan, Duojia

doi:10.1016/j.celrep.2017.11.076

Cited by 95 publications

(100 citation statements)

References 46 publications

(83 reference statements)

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“…Both increased kinase activity and increased phosphorylation of the human Tricornered-like kinase were observed following treatment of COS-1 cells with okadaic acid (Millward et al, 1999). Subsequent studies of yeast and fly NDR kinases reported similar effects in response to okadaic acid treatment, indicating that negative regulation of NDR kinases by phosphatase activity is conserved from yeast to humans (Mah et al, 2001;Chan et al, 2005;Lai et al, 2005;Hergovich et al, 2006a;Koike-Kumagai et al, 2009;Zheng et al, 2017).…”

Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 91%

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Duhart

Raftery

2020

Front. Cell Dev. Biol.

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Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mobdependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.

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Section: The Stripak Complex Is a Negative Regulator Of Hippo Signalingmentioning

confidence: 91%

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Duhart

Raftery

2020

Front. Cell Dev. Biol.

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“…It is believed that the scaffolding proteins, including SLMAP, SIKE, STRIP1 (FAM40A), STRIP2 (FAM40B), direct and uphold PP2A/Striatin phosphatase specificity, and loss of these proteins consequently disassemble the STRIPAK complex; leading to hyper-phosphorylation of PP2A/Striatin target proteins. This is, for example, observed upon loss of SLMAP, which induces hyperphosphorylation of MST1/2 kinases (Bae et al, 2017;Zheng et al, 2017;Tang et al, 2019), while loss of STRIP1 induces hyper-phosphorylation of MST3/4 kinases (Madsen et al, 2015).…”

Section: Introductionmentioning

confidence: 96%

“…Over the past few years, extensive functional and mechanistic research has been conducted to resolve the framework of the Striatin Interacting Phosphatase and Kinase (STRIPAK) complex. The accumulated findings have linked specific components of the complex to various biological functions including vesicular trafficking (Zhang et al, 2013;Lant et al, 2015), Golgi assembly (Kean et al, 2011), Hippo signaling (Ribeiro et al, 2010;Zheng et al, 2017), autophagy (Huang et al, 2017), cell migration (Madsen et al, 2015;Bazzi et al, 2017), and cell cycle control (Cornils et al, 2011;Frost et al, 2012;Kazmierczak-Baranska et al, 2015;Pandey et al, 2017). Substantiated by these findings, the STRIPAK complex is supervising embryogenesis and development (Lant et al, 2015;Madsen et al, 2015;Sakuma et al, 2015Sakuma et al, , 2016Bazzi et al, 2017;Pal et al, 2017;Zheng et al, 2017), circadian rhythms (Andreazza et al, 2015), type 2 diabetes (Chursa et al, 2017), and progression of cancer (Wong et al, 2014;Zhang et al, 2014;Madsen et al, 2015;Huang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27

Rodriguez-Cupello

Dam

Serini

et al. 2020

Front. Cell Dev. Biol.

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The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21 high /γH2AX low ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics in vitro paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.

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“…In contrast, a protein phosphatase PP2A complex called STRIPAK (Bae et al, ; Praskova et al, ; Zheng et al, ), Dachsous–Fat system (Irvine & Harvey, ; Mao et al, ), and extracellular matrix (ECM) sensing integrins (Chakraborty & Hong, ; Dobrokhotov, Samsonov, Sokabe, & Hirata, ) are responsible for inactivation of the Hippo pathway. In high‐energy conditions, enzyme O‐GlcNac transferase deactivates Hippo signaling allowing the expression of YAP‐regulated growth‐promoting genes (Peng et al, ).…”

Section: Overview Of the Hippo Signaling Networkmentioning

confidence: 99%

“…In contrast, a protein phosphatase PP2A complex called STRIPAK (Bae et al, 2017;Praskova et al, 2004;Zheng et al, 2017), Dachsous-Fat system (Irvine & Harvey, 2015;Mao et al, 2006), and extracellular matrix (ECM) sensing integrins (Chakraborty & Hong, 2018;Dobrokhotov, Samsonov, Sokabe, & Hirata, 2018) by HIF-1α in hypoxic conditions (Xiang et al, 2015).…”

Section: Upstream Regulators Of the Hippo Pathwaymentioning

confidence: 99%

The emerging role of Hippo signaling in neurodegeneration

Sahu

Mondal

2019

J of Neuroscience Research

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Neurodegeneration refers to the complex process of progressive degeneration or neuronal apoptosis leading to a set of incurable and debilitating conditions. Physiologically, apoptosis is important in proper growth and development. However, aberrant and unrestricted apoptosis can lead to a variety of degenerative conditions including neurodegenerative diseases. Although dysregulated apoptosis has been implicated in various neurodegenerative disorders, the triggers and molecular mechanisms underlying such untimely and faulty apoptosis are still unknown. Hippo signaling pathway is one such apoptosis‐regulating mechanism that has remained evolutionarily conserved from Drosophila to mammals. This pathway has gained a lot of attention for its tumor‐suppressing task, but recent studies have emphasized the soaring role of this pathway in inflaming neurodegeneration. In addition, strategies promoting inactivation of this pathway have aided in the rescue of neurons from anomalous apoptosis. So, a thorough understanding of the relationship between the Hippo pathway and neurodegeneration may serve as a guide for the development of therapy for various degenerative diseases. The current review focuses on the mechanism of the Hippo signaling pathway, its upstream and downstream regulatory molecules, and its role in the genesis of numerous neurodegenerative diseases. The recent efforts employing the Hippo pathway components as targets for checking neurodegeneration have also been highlighted.

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Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

Cited by 95 publications

References 46 publications

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27

The emerging role of Hippo signaling in neurodegeneration

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