MAP4K Interactome Reveals STRN4 as a Key STRIPAK Complex Component in Hippo Pathway Regulation

Seo, Gayoung; Han, Han; Vargas, Rebecca; Yang, Bing; Li, Xu; Wang, Wenqi

doi:10.1016/j.celrep.2020.107860

Cited by 40 publications

(53 citation statements)

References 55 publications

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“…Hpo/MST12 and MAP4Ks are negatively regulated by a large protein complex called STRIPAK that brings PP2A to dephosphorylate and inhibit these kinases ( Bae et al, 2017 ; Zheng et al, 2017 ; Kim J.W. et al, 2020 ; Seo et al, 2020 ; Tang et al, 2020 ). A recent study suggests that the STRIPAK complex integrates multiple upstream signals to regulate Hippo signaling pathway ( Chen et al, 2019 ).…”

Section: Overview Of the Canonical Hippo Signaling Pathwaymentioning

confidence: 99%

Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

Cho

Jen

2021

Front. Cell Dev. Biol.

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Initially identified in Drosophila, the Hippo signaling pathway has emerged as an evolutionarily conserved tumor suppressor pathway that controls tissue growth and organ size by simultaneously inhibiting cell proliferation and promoting cell death. Deregulation of Hippo pathway activity has been implicated in a wide range of human cancers. The core Hippo pathway consists of a kinase cascade: an upstream kinase Hippo (Hpo)/MST1/2 phosphorylates and activates a downstream kinase Warts (Wts)/Lats1/2, leading to phosphorylation and inactivation of a transcriptional coactivator Yki/YAP/Taz. Many upstream signals, including cell adhesion, polarity, mechanical stress, and soluble factors, regulate Hippo signaling through the kinase cascade, leading to change in the cytoplasmic/nuclear localization of Yki/YAP/Taz. However, recent studies have uncovered other mechanisms that regulate Yki/YAP/Taz subcellular localization, stability, and activity independent of the Hpo kinase cascade. These mechanisms provide additional layers of pathway regulation, nodes for pathway crosstalk, and opportunities for pathway intervention in cancer treatment and regenerative medicine.

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Section: Overview Of the Canonical Hippo Signaling Pathwaymentioning

confidence: 99%

Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

Cho

Jen

2021

Front. Cell Dev. Biol.

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“…Different combinations of these core proteins and accessory proteins results in the formation of different STRIPAK complexes. And it was reported that the STRIPAK complex plays many important roles in embryo development, cancer, diabetes, autism, and many other diseases, and regulates many important signaling pathways and cellular processes ( Hwang and Pallas, 2014 ; Wong et al, 2014 ; Zhang et al, 2014 ; Lant et al, 2015 ; Madsen et al, 2015 ; Sakuma et al, 2015 , 2016 ; Bazzi et al, 2017 ; Chursa et al, 2017 ; Huang et al, 2017 ; Pal et al, 2017 ; Zheng et al, 2017 ; Elramli et al, 2019 ; Kuck et al, 2019 ; Tang et al, 2019 ; Rodriguez-Cupello et al, 2020 ; Seo et al, 2020 ; Stein et al, 2020 ; Xie et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…The STRIPAK complex, an evolutionarily conserved supramolecular complex, is involved in many important physiological processes and diseases, including embryogenesis and development ( Lant et al, 2015 ; Sakuma et al, 2015 , 2016 ; Bazzi et al, 2017 ; Pal et al, 2017 ; Zheng et al, 2017 ), type 2 diabetes ( Chursa et al, 2017 ), and cancer progression ( Wong et al, 2014 ; Zhang et al, 2014 ; Madsen et al, 2015 ; Huang et al, 2017 ; Rodriguez-Cupello et al, 2020 ). The STRIPAK complex has several different formations depending on the combinations of different, mutually exclusive accessory proteins to the STRIPAK core components ( Hwang and Pallas, 2014 ; Kuck et al, 2019 ; Rodriguez-Cupello et al, 2020 ; Seo et al, 2020 ; Stein et al, 2020 ; Xie et al, 2020 ). Several important proteins combine to form the core STRIPAK components, including a striatin family member, the PP2A A/C heterodimer, Mob3, Strip1 or Strip2, and a GCKIII kinase bound via Ccm3 ( Goudreault et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Strip1 Expression in Mouse Cochlear Hair Cells

et al. 2021

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Striatin-interacting protein 1 (Strip1) is a core component of the striatin interacting phosphatase and kinase (STRIPAK) complex, which is involved in embryogenesis and development, circadian rhythms, type 2 diabetes, and cancer progression. However, the expression and role of Strip1 in the mammalian cochlea remains unclear. Here we studied the expression and function of Strip1 in the mouse cochlea by using Strip1 knockout mice. We first found that the mRNA and protein expression of Strip1 increases as mice age starting from postnatal day (P) 3 and reaches its highest expression level at P30 and that the expression of Strip1 can be detected by immunofluorescent staining starting from P14 only in cochlear HCs, and not in supporting cells (SCs). Next, we crossed Strip1 heterozygous knockout (Strip +/−) mice to obtain Strip1 homozygous knockout (Strip1−/−) mice for studying the role of Strip1 in cochlear HCs. However, no Strip1−/− mice were obtained and the ratio of Strip +/− to Strip1+/+ mice per litter was about 2:1, which suggested that homozygous Strip1 knockout is embryonic lethal. We measured hearing function and counted the HC number in P30 and P60 Strip +/− mice and found that they had normal hearing ability and HC numbers compared to Strip1+/+ mice. Our study suggested that Strip1 probably play important roles in HC development and maturation, which needs further study in the future.

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“…Animal studies suggest that STRIPAK might be involved in cell cycle control, cell adhesion, migration, epithelial integrity and epithelial-to-mesenchymal transition. STRN4, by inhibition of MAP4K4 kinase, is considered the key regulator inhibiting the Hippo pathway involved in asthma pathogenesis 108 . In T-cells, de ciency of MAP4K4 results in Th17 differentiation with IL-6 and IL-17 expression 109 .…”

Section: Striatin-4 (Strn4)mentioning

confidence: 99%

Integration of Airway Inflammation and Remodeling Mechanisms Specific to Eosinophilic Asthma Through Differential Co-Expression of Genes in Bronchial Brush Biopsy Samples

Koźlik

Buregwa-Czuma

Zawlik

et al. 2021

Preprint

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Background Heterogeneity of asthma complicates search for targeted treatment against airway hyperresponsiveness and remodeling. We conducted a systems biology approach study to establish differential co-expression of genes (DCG) in eosinophilic and non-eosinophilic asthma patients and infer their role in the disease. Materials and Methods N = 40 Caucasian adult moderate to severe non-smoking asthma patients (half with eosinophilic asthma) undergone bronchial brush biopsy sampling for mRNA expression using hybridization to cDNA microarray. Mechanistic interpretation of DCG was inferred from existing literature. Results Differentially co-expressed genes bear significance in airway viral infection (ATP1B1, EPS15), arachidonic acid metabolism (CLC, FADS6), cell migration (EPS8L1, STOML3, RhoBTB2), surface receptors endocytosis (STRN4, EPS15, ATP1B1) or decreased expression (CCT7), oxidative stress (DIO3, RhoBTB2), decreased adhesion (ATP1B1, RAPH1, STOML3), epithelial-mesenchymal transition (ASB3, RADX, CCT7, MRPL14, PPP2R3B, RPS13, SLC19A1), myofibroblast differentiation (CCT7), smooth muscle proliferation (ASB3, ATP1B1), airway hyperreactivity (RECK, STOML3, ATP1B1, OR52I1), extracellular matrix remodeling (FBN3, RECK), angiogenesis (GPI, RhoBTB2) and neuronal pathogenesis of asthma (OR52I1, STRN4, TTC3P1, GPI, CABP5) and were linked to asthma in genome- (MRPL14, ASB3, RPS13) and epigenome-wide (CLC, EPS15, GPI, SSCRB4, STRN4) association studies. Signaling pathways involved (especially TGF-β/Smad2/3) are inferred from the co-expression pattern. Conclusion Activity of genes and pathways of known or tentative role in asthma pathogenesis was established in regard to a condition cognizable in clinical practice.

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MAP4K Interactome Reveals STRN4 as a Key STRIPAK Complex Component in Hippo Pathway Regulation

Abstract: Highlights d Proteomic analysis defines the human MAP4K family interactome d The STRIPAK complex component STRN4 interacts with and inhibits MAP4Ks d STRN4 is a positive regulator of YAP d Elevated STRN4 expression is associated with YAP activation in endometrial cancer

Cited by 40 publications

References 55 publications

Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

Characterization of Strip1 Expression in Mouse Cochlear Hair Cells

Integration of Airway Inflammation and Remodeling Mechanisms Specific to Eosinophilic Asthma Through Differential Co-Expression of Genes in Bronchial Brush Biopsy Samples

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