Striatins Contain a Noncanonical Coiled Coil That Binds Protein Phosphatase 2A A Subunit to Form a 2:2 Heterotetrameric Core of Striatin-interacting Phosphatase and Kinase (STRIPAK) Complex

Chen, Cuicui; Shi, Zhubing; Zhang, Wenqing; Chen, Min; He, Feng; Zhang, Zhenzhen; Wang, Yicui; Mao, Feng; Wang, Wenjia; Zhao, Yun; Brown, Jerry H.; Shi, Jianzhong; Zhou, Zhaocai

doi:10.1074/jbc.m113.529297

Cited by 44 publications

(35 citation statements)

References 55 publications

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“…Although STRN3 gain-of-binding to mutant Aa could not explain hyperphosphorylation of Akt, p70S6K, or GSK3b in mutant Aa expressing HEC-1-A cells, it remains possible that this gain-of-function mechanism still contributes to the stronger oncogenic phenotype of these cells. The role of PP2A striatins within several STRIPAK complexes is indeed considered to be oncogenic, via dephosphorylation of Mst1/2 and Mst3/4 kinases (51-53), impacting, e.g., on regulation of NF-kB (54), Hippo (23,24), and MEK/ERK (51,53). The reported role of PP2A striatins in regulating cancer cell migration and invasion (55) remains worthwhile to follow up, particularly because serous uterine tumors are highly metastatic.…”

Section: Discussionmentioning

confidence: 99%

Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth

et al. 2016

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Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3β, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3β phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth

et al. 2016

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“…This raises the obvious question of whether in fact the surfaces of coiled‐coil proteins are widely used as molecular scaffolds. Surprisingly, examples of their use to scaffold multi‐subunit protein complexes or to recruit enzymatic activities are relatively scarce. Analogous to the interaction of Shroom with ROCK, the coiled‐coil domain of MRCK has been proposed to contain a binding site for the leucine repeat adaptor protein 35a (LRAP35a), which links MRCK to MYO18A in a tripartite complex responsible for the assembly of lamellar actomyosin bundles essential for cell protrusion .…”

Section: Less Common Than You Might Think – Coiled‐coils As Molecularmentioning

confidence: 99%

Coiled‐coils: The long and short of it

2016

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Coiled‐coils are found in proteins throughout all three kingdoms of life. Coiled‐coil domains of some proteins are almost invariant in sequence and length, betraying a structural and functional role for amino acids along the entire length of the coiled‐coil. Other coiled‐coils are divergent in sequence, but conserved in length, thereby functioning as molecular spacers. In this capacity, coiled‐coil proteins influence the architecture of organelles such as centrioles and the Golgi, as well as permit the tethering of transport vesicles. Specialized coiled‐coils, such as those found in motor proteins, are capable of propagating conformational changes along their length that regulate cargo binding and motor processivity. Coiled‐coil domains have also been identified in enzymes, where they function as molecular rulers, positioning catalytic activities at fixed distances. Finally, while coiled‐coils have been extensively discussed for their potential to nucleate and scaffold large macromolecular complexes, structural evidence to substantiate this claim is relatively scarce.

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“…Some of the key fungal STRIPAK subunits (Table 1), namely phocein/Mob3, are known to associate with striatin, primarily with the C-terminal region (Bloemendal et al, 2012). Meanwhile, studies have also shown that the CC domain plays an important role in protein recruitment and structural assembly, which can influence overall STRIPAK function in mammalian systems (Chen et al, 2014;Gordon et al, 2011). One of our key aims was to identify F. verticillioides proteins that primarily interact with the Fsr1 CC motif and to test whether these proteins are involved in the regulation of stalk rot virulence.…”

Section: Identification Of New Fsr1-interacting Proteins In F Verticmentioning

confidence: 99%

Fsr1, a striatin homologue, forms an endomembrane‐associated complex that regulates virulence in the maize pathogen Fusarium verticillioides

Zhang

Mukherjee

Kim

et al. 2017

Molecular Plant Pathology

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Fsr1, a homologue of mammalian striatin, containing multiple protein-binding domains and a coiled-coil (CC) domain, is critical for Fusarium verticillioides virulence. In mammals, striatin interacts with multiple proteins to form a STRIPAK (striatin-interacting phosphatase and kinase) complex that regulates a variety of developmental processes and cellular mechanisms. In this study, we identified the homologue of a key mammalian STRIPAK component STRIP1/2 (striatin-interacting proteins 1 and 2) in F. verticillioides, FvStp1, which interacts with Fsr1 in vivo. Gene deletion analysis indicates that FvStp1 is critical for F. verticillioides stalk rot virulence. In addition, we identified three proteins, designated FvCyp1, FvScp1 and FvSel1, which interact with the Fsr1 CC domain via a yeast two-hybrid screen. Importantly, FvCyp1, FvScp1 and FvSel1 co-localize to endomembrane structures, each having a preferred localization in the cell, and they are all required for F. verticillioides stalk rot virulence. Moreover, these proteins are necessary for the correct localization of Fsr1 to the endoplasmic reticulum (ER) and nuclear envelope. Thus, we identified several novel components in the STRIPAK complex that regulates F. verticillioides virulence, and propose that the correct organization and localization of Fsr1 are critical for STRIPAK complex function.

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Striatins Contain a Noncanonical Coiled Coil That Binds Protein Phosphatase 2A A Subunit to Form a 2:2 Heterotetrameric Core of Striatin-interacting Phosphatase and Kinase (STRIPAK) Complex

Cited by 44 publications

References 55 publications

Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth

Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth

Coiled‐coils: The long and short of it

Fsr1, a striatin homologue, forms an endomembrane‐associated complex that regulates virulence in the maize pathogen Fusarium verticillioides

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