STRIPAK, a highly conserved signaling complex, controls multiple eukaryotic cellular and developmental processes and is linked with human diseases

Kück, Ulrich; Radchenko, Daria; Teichert, Ines

doi:10.1515/hsz-2019-0173

Cited by 93 publications

(99 citation statements)

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“…The striatin‐interacting phosphatases and kinases (STRIPAK) complex is a highly conserved macromolecular signaling complex that is involved in numerous cellular and developmental eukaryotic processes. In humans, malfunctions of STRIPAK subunits are linked with various diseases and cancer, whereas in eukaryotic microorganisms, several processes, such as cell fusion, fruiting body formation, as well as symbiotic and pathogenic interactions, are controlled by STRIPAK (Kück, Radchenko, & Teichert, ). Although architecture, function and regulation of STRIPAK are well characterized in diverse experimental systems (Hwang & Pallas, ; Kück, Beier, & Teichert, ; Shi, Jiao, & Zhou, ), our understanding of how STRIPAK regulates the phosphorylation of developmental proteins is still rudimentary.…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomic analysis of STRIPAK mutants identifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important in fungal sexual development and polarized growth

Märker

Blank-Landeshammer

Beier-Rosberger

et al. 2020

Molecular Microbiology

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The highly conserved striatin‐interacting phosphatases and kinases (STRIPAK) complex regulates phosphorylation/dephosphorylation of developmental proteins in eukaryotic microorganisms, animals and humans. To first identify potential targets of STRIPAK, we performed extensive isobaric tags for relative and absolute quantification‐based proteomic and phosphoproteomic analyses in the filamentous fungus Sordaria macrospora. In total, we identified 4,193 proteins and 2,489 phosphoproteins, which are represented by 10,635 phosphopeptides. By comparing phosphorylation data from wild type and mutants, we identified 228 phosphoproteins to be regulated in all three STRIPAK mutants, thus representing potential targets of STRIPAK. To provide an exemplarily functional analysis of a STRIPAK‐dependent phosphorylated protein, we selected CLA4, a member of the conserved p21‐activated kinase family. Functional characterization of the ∆cla4 deletion strain showed that CLA4 controls sexual development and polarized growth. To determine the functional relevance of CLA4 phosphorylation and the impact of specific phosphorylation sites on development, we next generated phosphomimetic and ‐deficient variants of CLA4. This analysis identified (de)phosphorylation of a highly conserved serine (S685) residue in the catalytic domain of CLA4 as being important for fungal cellular development. Collectively, these analyses significantly contribute to the understanding of the mechanistic function of STRIPAK as a phosphatase and kinase signaling complex.

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Section: Introductionmentioning

confidence: 99%

Phosphoproteomic analysis of STRIPAK mutants identifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important in fungal sexual development and polarized growth

Märker

Blank-Landeshammer

Beier-Rosberger

et al. 2020

Molecular Microbiology

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“…The STRIPAK complex, which includes striatin, a subunit of the PP2A enzyme, is associated with numerous biological roles ranging from cell signaling to developmental processes [2]. To study the biological function of striatin, a knockout mouse was generated.…”

Section: Resultsmentioning

confidence: 99%

“…The striatin-interacting phosphatase and kinase (STRIPAK) complex is a multimolecular protein complex involved in numerous biological functions and has been implicated in a number of human diseases [1][2][3]. STRIPAK complexes regulate phosphorylation of diverse proteins and interact with conserved signaling pathways [2]. The mammalian striatin family is ubiquitously expressed and consists of striatin (STRN), SG2NA (STRN3), and Zinedin (STRN4).…”

Section: Introductionmentioning

confidence: 99%

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Ponniah

Taiber

Caspi

et al. 2020

Preprint

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Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell junctional integrity. Since adhesion is crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea.Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Importantly, striatin-deficient mice show aberrant ribbon synapse maturation that may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system. Medicine Grant for Collaborative Research (RL, RRA). We thank Ana Turchetti-Maia and Kevin Ohlemiller for their advice for EP recordings, Vered Holdengreber for help with electron microscopy, and Ronen Siman-Tov for help with the mice. Author contributions KBA and RRA conceived the project. RAL generated the Striatin knockout mice. PTNP designed and performed the genotyping, dissections of inner ears, ABR, SEM, confocal imaging, Western blots, and quantification of ribbon synapses. MR and ST performed the endocochlear potential experiments. ST and TK-B aided with dissections and SEM imaging analysis. MC and AAD aided with image analysis, experimental design and organizing the data. PTNP, ST, KBA, and RRA wrote the manuscript. KBA and RRA supervised the work.

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“…The striatin-interacting phosphatases and kinases (STRIPAK) complex is a highly conserved macromolecular signaling complex that is involved in numerous cellular and developmental eukaryotic processes. In humans, malfunctions of STRIPAK subunits are linked with various diseases and cancer; whereas, in eukaryotic microorganisms, several processes, such as cell fusion, fruiting body formation, as well as symbiotic and pathogenic interactions, are controlled by STRIPAK (Kück et al 2019). Although architecture, function, and regulation of STRIPAK are well characterized in diverse experimental systems (Hwang and Pallas 2014; Kück et al 2016; Shi et al 2016), our understanding of how STRIPAK regulates the phosphorylation of developmental proteins is still rudimentary.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have used a large set of mutant and deletion strains to identify and structurally and functionally characterize STRIPAK subunits in the model fungus Sordaria macrospora. In extensive tandem affinity purification followed by mass spectrometry (TAP-MS) and yeast-two-hybrid analyses, we identified the structural (PP2AA) and catalytic (PP2Ac) subunits of PP2A, the B‴ regulatory subunit of PP2A (striatin), the striatin-interacting protein PRO22, SmMOB3, which is homologous to the mammalian vesicular trafficking protein Mob3, and PRO45, a homologue of the mammalian sarcolemmal membrane-associated protein SLMAP (Kück et al 2016; Kück et al 2019). Recently, a STRIPAK complex interactor 1 (SCI1) was identified that exhibited structural similarity to SIKE, a coiled-coil protein that serves as a negative regulator of pathological cardiac hypertrophy in humans (Reschka et al 2018).…”

Section: Introductionmentioning

confidence: 99%

iTRAQ-based proteomic and phosphoproteomic analyses of STRIPAK mutants from the fungusSordaria macrosporaidentifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important for sexual development and polarized growth

Märker

Blank-Landeshammer

Beier-Rosberger

et al. 2019

Preprint

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1 from the fungus Sordaria macrospora identifies a conserved serine phosphorylation 2 site in PAK kinase CLA4 to be important for sexual development and polarized 3 growth 4 5 6 Summary 22The highly conserved striatin-interacting phosphatases and kinases (STRIPAK) 23 complex regulates phosphorylation of developmental proteins in eukaryotic 24 microorganisms, animals, and humans. To first identify potential targets of 25 STRIPAK, we performed extensive isobaric tags for relative and absolute 26 quantification (iTRAQ)-based proteomic and phosphoproteomic analyses in the 27 filamentous fungus Sordaria macrospora. In total, we identified 4,193 proteins and 28 2,489 phosphoproteins, which are represented by 10,635 phosphopeptides. By 29 comparing phosphorylation data from wild-type and mutants, we identified 228 30 phosphoproteins to be regulated in all three STRIPAK mutants, thus representing 31 potential targets of STRIPAK. To provide an exemplarily functional analysis of a 32 STRIPAK-dependent phosphorylated protein, we selected CLA4, a member of the 33 conserved p21-activated kinase (PAK) family. Functional characterization of the 34 ∆cla4 deletion strain showed that CLA4 controls sexual development and polarized 35 growth. To determine the functional relevance of CLA4 phosphorylation and the 36 impact of specific phosphorylation sites on development, we next generated 37 phospho-mimetic and -deficient variants of CLA4. This analysis identified 38 (de)phosphorylation of a highly conserved serine (S685) residue in the catalytic 39 domain of CLA4 as being important for fungal cellular development. Collectively, 40 these analyses significantly contribute to the understanding of the mechanistic 41 function of STRIPAK as a phosphatase and kinase signaling complex. 42 43 44 45 46 Results 102 In this work, detailed iTRAQ-based proteomic and phosphoproteomic analyses of 103 the wild-type and three different STRIPAK deletion strains led to the identification of 104 putative dephosphorylation targets of the STRIPAK complex in S. macrospora. 105 Importantly, functional characterization of the PAK kinase CLA4, a target protein of 106 STRIPAK deciphers their role in fungal cellular development. 107 108 iTRAQ-based proteomic and phosphoproteomic analyses revealed putative 109 dephosphorylation targets of the STRIPAK complex 110 To identify dephosphorylation targets of STRIPAK, we performed iTRAQ-based LC-111 MS/MS proteomic and phosphoproteomic analyses to directly compare relative 112 changes in protein expression (Fig. 1). The iTRAQ strategy is based on the N-113 terminal labelling of peptides with up to eight amino group-reactive reagents coupled 114 to different reporter and balancer groups (Ross et al. 2004; Wu et al. 2006). Thus, 115 we were able to conduct a simultaneous analysis of up to eight different cultural 116 samples. While these isobaric tags have the same mass, fragmentation during 117 tandem MS (MS/MS) leads to the generation of mass-specific reporter ions whose 118 abundances are used for protein quantific...

show abstract

STRIPAK, a highly conserved signaling complex, controls multiple eukaryotic cellular and developmental processes and is linked with human diseases

Cited by 93 publications

References 106 publications

Phosphoproteomic analysis of STRIPAK mutants identifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important in fungal sexual development and polarized growth

Phosphoproteomic analysis of STRIPAK mutants identifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important in fungal sexual development and polarized growth

Striatin is required for hearing and affects inner hair cells and ribbon synapses

iTRAQ-based proteomic and phosphoproteomic analyses of STRIPAK mutants from the fungusSordaria macrosporaidentifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important for sexual development and polarized growth

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