GRP94 Is Essential for Mesoderm Induction and Muscle Development Because It Regulates Insulin-like Growth Factor Secretion

Wanderling, Sherry; Simen, Birgitte B.; Ostrovsky, Olga; Ahmed, Noreen; Vogen, Shawn M.; Gidalevitz, Tali; Argon, Yair

doi:10.1091/mbc.e07-03-0275

Cited by 131 publications

(156 citation statements)

References 67 publications

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“…The line 14.1 is a grp94 Ϫ/Ϫ mouse embryonic fibroblast (32). The cells were transfected on fibronectin-coated 35-mm glass bottom culture dishes (MatTek).…”

Section: Methodsmentioning

confidence: 99%

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An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells

Ostrovsky

Makarewich

Snapp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone for which only few client proteins and no cofactors are known and whose mode of action is unclear. To decipher the mode of GRP94 action in vivo, we exploited our finding that GRP94 is necessary for the production of insulin-like growth factor (IGF)-II and developed a cell-based functional assay. Grp94 ؊/؊ cells are hypersensitive to serum withdrawal and die. This phenotype can be complemented either with exogenous IGF-II or by expression of functional GRP94. Fusion proteins of GRP94 with monomeric GFP (mGFP) or mCherry also rescue the viability of transiently transfected, GRP94-deficient cells, demonstrating that the fusion proteins are functional. Because these constructs enable direct visualization of chaperone-expressing cells, we used this survival assay to assess the activities of GRP94 mutants that are defective in specific biochemical functions in vitro. Mutations that abolish binding of adenosine nucleotides cannot support growth in serumfree medium. Similarly, mutations of residues needed for ATP hydrolysis also render GRP94 partially or completely nonfunctional. In contrast, an N-terminal domain mutant that cannot bind peptides still supports cell survival. Thus the peptide binding activity in vitro can be uncoupled from the chaperone activity toward IGF in vivo. This mutational analysis suggests that the ATPase activity of GRP94 is essential for chaperone activity in vivo and that the essential protein-binding domain of GRP94 is distinct from the N-terminal domain.endoplasmic reticulum ͉ peptide hormones ͉ protein folding

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“…The line 14.1 is a grp94 Ϫ/Ϫ mouse embryonic fibroblast (32). The cells were transfected on fibronectin-coated 35-mm glass bottom culture dishes (MatTek).…”

Section: Methodsmentioning

confidence: 99%

“…removal, and undergo rapid apoptosis (14,32). Unlike GRP94-containing cells (WT), grp94 Ϫ/Ϫ (KO) ES cells cannot respond to the stress by producing the growth factor IGF-II (14).…”

mentioning

confidence: 99%

An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells

Ostrovsky

Makarewich

Snapp

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…GRP94 is an essential gene in metazoans as it is required for early developmental stages in mice, Arabidopsis, Drosophila, and C. elegans (Ishiguro et al 2002;Wanderling et al 2007;Baviskar and Shields 2010;Maynard et al 2010), yet many unanswered questions remain about its role in ER homeostasis and its mechanism of action. Surprisingly the activity of GRP94 in unicellular organisms is not essential or in some cases such as yeast, it is even absent.…”

Section: Classical Chaperonesmentioning

confidence: 99%

“…Some of the maturing substrates that GRP94 associates with include immunoglobulin family members, integrins, thyroglobulin, and insulin-like growth factors (Randow and Seed 2001;Berwin et al 2003;Srivastava 2006;Ostrovsky et al 2009). Although mouse knockouts are embryonic lethal, tissue-specific knockouts to the musculature allow the mice to survive, but they are much smaller (Wanderling et al 2007). This has been attributed to the lack of production of IGFs, obligate substrates of GRP94.…”

Section: Classical Chaperonesmentioning

confidence: 99%

Protein Folding in the Endoplasmic Reticulum

Braakman

Hebert

2013

Cold Spring Harbor Perspectives in Biology

415

349

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In this article, we will cover the folding of proteins in the lumen of the endoplasmic reticulum (ER), including the role of three types of covalent modifications: signal peptide removal, Nlinked glycosylation, and disulfide bond formation, as well as the function and importance of resident ER folding factors. These folding factors consist of classical chaperones and their cochaperones, the carbohydrate-binding chaperones, and the folding catalysts of the PDI and proline cis -trans isomerase families. We will conclude with the perspective of the folding protein: a comparison of characteristics and folding and exit rates for proteins that travel through the ER as clients of the ER machinery.

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“…HSP90β is constitutively and ubiquitously expressed, whereas HSP90α is heat inducible and tissue specific (13). The HSP90 homolog GRP94 is found in the endoplasmic reticulum where it is essential for the maturation and secretion of insulin-like growth factors (14). TRAP1 is localized in mitochondria, where it functions as a protective factor against oxidative stress (15,16).…”

mentioning

confidence: 99%

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Solier

Kohn²,

Scroggins³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The “apoptotic ring” is characterized by the phosphorylation of histone H2AX at serine 139 (γ-H2AX) by DNA-dependent protein kinase (DNA-PK). The γ-H2AX apoptotic ring differs from the nuclear foci patterns observed in response to DNA-damaging agents. It contains phosphorylated DNA damage response proteins including activated Chk2, activated ATM, and activated DNA-PK itself but lacks MDC1 and 53BP1, which are required to initiate DNA repair. Because DNA-PK can phosphorylate heat shock protein 90α (HSP90α) in biochemical assays, we investigated whether HSP90α is involved in the apoptotic ring. Here we show that HSP90α is phosphorylated by DNA-PK on threonines 5 and 7 early during apoptosis and that both phosphorylated HSP90α and DNA-PK colocalize in the apoptotic ring. We also show that DNA-PK is a client of HSP90α and that HSP90α is required for full DNA-PK activation, γ-H2AX formation, DNA fragmentation, and apoptotic body formation. In contrast, HSP90 inhibition by geldanamycin markedly enhances TRAIL-induced DNA-PK and H2AX activation. Together, our results reveal that HSP90α is a substrate and chaperone of DNA-PK in the apoptotic response. The response of phosphorylated HSP90α to TRAIL and its localization to the γ-H2AX ring represent epigenetic features of apoptosis that offer insights for studying and monitoring nuclear apoptosis.

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GRP94 Is Essential for Mesoderm Induction and Muscle Development Because It Regulates Insulin-like Growth Factor Secretion

Cited by 131 publications

References 67 publications

An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells

An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells

Protein Folding in the Endoplasmic Reticulum

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

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