TGF-β Signaling in Development

Kitisin, Krit; Saha, Tapas Kumar; Blake, Tiffany; Golestaneh, Nady; Deng, Merlyn; Kim, Christine M.; Shetty, Kirti; Mishra, Bibhuti; Mishra, Lopa

doi:10.1126/stke.3992007cm1

Cited by 172 publications

(133 citation statements)

References 23 publications

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“…However, the near-complete rescue of the combined GADD34 and CReP deficiency by the Eif2a S51A mutation argues against a prominent role for the PPP1R15 proteins in regulating the activity of these pathways, as the severe perturbation of mammalian development associated with deregulated TGF␤ (32) or TSC activity (33)(34)(35) would not be rescued by the Eif2a S51A mutation. Furthermore, we detected no differences in the activity of S6 kinase, a downstream target of the TSC complex, between wild-type cells and those lacking both PPP1r15 genes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

Harding

Zhang

Scheuner³

et al. 2009

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

242

211

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Diverse cellular stress responses are linked to phosphorylation of serine 51 on the alpha subunit of translation initiation factor 2. The resultant attenuation of protein synthesis and activation of gene expression figure heavily in the adaptive response to stress, but dephosphorylation of eIF2(␣P), which terminates signaling in this pathway, is less well understood. GADD34 and CReP, the products of the related mammalian genes Ppp1r15a and Ppp1r15b, can recruit phosphatase catalytic subunits of the PPP1 class to eIF2(␣P), but the significance of their contribution to its dephosphorylation has not been explored systematically. Here we report that unlike Ppp1r15a mutant mice, which are superficially indistinguishable from wild type, Ppp1r15b ؊/؊ mouse embryos survive gestation but exhibit severe growth retardation and impaired erythropoiesis, and loss of both Ppp1r15 genes leads to early embryonic lethality. These loss-of-function phenotypes are rescued by a mutation, Eif2a S51A , that prevents regulated phosphorylation of eIF2␣. These findings reveal that the essential process of eIF2(␣P) dephosphorylation is the predominant role of PPP1R15 proteins in mammalian development.mouse genetics ͉ phosphatase regulation ͉ protein synthesis ͉ unfolded protein response

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Section: Resultsmentioning

confidence: 99%

Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

Harding

Zhang

Scheuner³

et al. 2009

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

242

211

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“…In addition, genetic disruption of BMPs can result in skeletal and extraskeletal abnormalities. (12) More than 20 members of the BMP family have been identified to date, including BMP-2, -4, -6, and -7, that have osteogenic properties. (13) A new BMP (BMP-9) has been identified recently and has been shown to be the most potent BMP.…”

Section: Introductionmentioning

confidence: 99%

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

Leblanc

Trensz

Haroun

et al. 2010

Journal of Bone and Mineral Research

112

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Heterotopic ossification (HO) is defined as the formation of bone inside soft tissue. Symptoms include joint stiffness, swelling, and pain. Apart from the inherited form, the common traumatic form generally occurs at sites of injury in damaged muscles and is often associated with brain injury. We investigated bone morphogenetic protein 9 (BMP-9), which possesses a strong osteoinductive capacity, for its involvement in muscle HO physiopathology. We found that BMP-9 had an osteoinductive influence on mouse muscle resident stromal cells by increasing their alkaline phosphatase activity and bone-specific marker expression. Interestingly, BMP-9 induced HO only in damaged muscle, whereas BMP-2 promoted HO in skeletal muscle regardless of its state. The addition of the soluble form of the ALK1 protein (the BMP-9 receptor) significantly inhibited the osteoinductive potential of BMP-9 in cells and HO in damaged muscles. BMP-9 thus should be considered a candidate for involvement in HO physiopathology, with its activity depending on the skeletal muscle microenvironment. ß

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“…TGF-βs inhibit the proliferation of normal epithelial cells but display both tumor-suppressing and tumor-promoting activities during cancer development (31). The binding of TGF-β1-3 to TGF-β receptor-2 (TGFBR2) activates TGFBR1, which activates the SMADs pathway transmitting the signal into the nucleus (32). Nuclear SMAD2/3 activity is enhanced by nuclear translocation of YAP1/TAZ, whereas cytoplasmic YAP1/TAZ prevents the nuclear accumulation of SMADs (33,34).…”

Section: Significancementioning

confidence: 99%

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Nishio

Sugimachi

Goto

et al. 2015

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

166

160

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Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

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TGF-β Signaling in Development

Cited by 172 publications

References 23 publications

Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

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