FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2004993211> ?p ?o ?g. }

• W2004993211 endingPage "400" @default.
• W2004993211 startingPage "399" @default.
• W2004993211 abstract "The protein kinase Akt occupies a central position in multiple signaling pathways. Although numerous Akt substrates have been identified, less is known about the factors that regulate specific cellular responses to Akt signaling. In this issue, Schenck et al., 2008Schenck A. Goto-Silva L. Collinet C. Rhinn M. Giner A. Habermann B. Brand M. Zerial M. Cell. 2008; (this issue)PubMed Google Scholar demonstrate that the endosomal protein Appl1 modulates Akt's substrate selectivity to promote cell survival during zebrafish development. The protein kinase Akt occupies a central position in multiple signaling pathways. Although numerous Akt substrates have been identified, less is known about the factors that regulate specific cellular responses to Akt signaling. In this issue, Schenck et al., 2008Schenck A. Goto-Silva L. Collinet C. Rhinn M. Giner A. Habermann B. Brand M. Zerial M. Cell. 2008; (this issue)PubMed Google Scholar demonstrate that the endosomal protein Appl1 modulates Akt's substrate selectivity to promote cell survival during zebrafish development. The serine/threonine protein kinase Akt is activated by a wide range of stimuli, such as growth factors and cytokines (Manning and Cantley, 2007Manning B.D. Cantley L.C. Cell. 2007; 129: 1261-1274Abstract Full Text Full Text PDF PubMed Scopus (4269) Google Scholar), and has been implicated in many aspects of cellular regulation, including cell survival, growth, proliferation, migration, and metabolism. Likewise, numerous Akt substrates have been identified that mediate these effects (Figure 1). Because phosphorylation of specific Akt substrates determines the cellular response, a major question in Akt signaling is how substrate selectivity is achieved. In this issue, Schenck et al., 2008Schenck A. Goto-Silva L. Collinet C. Rhinn M. Giner A. Habermann B. Brand M. Zerial M. Cell. 2008; (this issue)PubMed Google Scholar provide evidence for the role of spatial regulation in Akt signaling. They show that the binding of Akt to the endosomal protein Appl1 contributes to Akt's substrate selectivity and promotes cell survival in zebrafish development. Human APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper) was originally identified as an Akt-interacting protein (Mitsuuchi et al., 1999Mitsuuchi Y. Johnson S.W. Sonoda G. Tanno S. Golemis E.A. Testa J.R. Oncogene. 1999; 18: 4891-4898Crossref PubMed Scopus (168) Google Scholar). Subsequent studies have established that APPL1 is a direct downstream effector of Rab5 (Miaczynska et al., 2004Miaczynska M. Christoforidis S. Giner A. Shevchenko A. Uttenweiler-Joseph S. Habermann B. Wilm M. Parton R.G. Zerial M. Cell. 2004; 116: 445-456Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar), a GTPase involved in endocytosis. In new work using a zebrafish model, Schenck et al. now show that downregulation of Appl1 or Appl2 by antisense morpholinos markedly increases apoptosis in tissues that normally have high levels of expression of Appl1 and Appl2 (Schenck et al., 2008Schenck A. Goto-Silva L. Collinet C. Rhinn M. Giner A. Habermann B. Brand M. Zerial M. Cell. 2008; (this issue)PubMed Google Scholar). A role for Appl2 in cell survival during development is further supported by genetic mutation analyses. Previous work has shown that activity of mammalian Akt is enhanced by binding to APPL1 in response to various signals. Similarly, Schenck et al. show that activation of Akt by growth factor stimulation is diminished by morpholino knockdown of Appl1 in zebrafish. Based on these and other findings the authors conclude that Appl1 is essential for the prosurvival function of Akt. They then examined the effect of depleting Appl1 on the phosphorylation of two Akt substrates, glycogen synthase kinase 3 (Gsk3) and tuberous sclerosis protein 2 (Tsc2). Surprisingly, inactivation of Appl1 only decreases the phosphorylation of Gsk3 but not Tsc2 (Figure 1), suggesting that Appl1 may affect the substrate selectivity of Akt in vivo. The colocalization of APPL1 with Akt and GSK3, but not TSC2, further supports the notion that Appl1 regulates Akt substrate selectivity (Schenck et al., 2008Schenck A. Goto-Silva L. Collinet C. Rhinn M. Giner A. Habermann B. Brand M. Zerial M. Cell. 2008; (this issue)PubMed Google Scholar). Human APPL1 is localized in multiple cellular compartments, including endosomes (Miaczynska et al., 2004Miaczynska M. Christoforidis S. Giner A. Shevchenko A. Uttenweiler-Joseph S. Habermann B. Wilm M. Parton R.G. Zerial M. Cell. 2004; 116: 445-456Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). Schenck et al. show that stimulation of HeLa cells by insulin-like growth factor 1 (IGF-1) results in a transient colocalization of Akt and APPL1 in endosomes. Importantly, a fraction of APPL1-positive endosomes also display positive staining for GSK3, and IGF-1 treatment results in rapid dissociation of GSK3 from the APPL1-positive endosomes. Furthermore, coexpression of constitutively active Rab5 induces formation of large endosomes and a striking recruitment of GSK3 to endosomes with APPL1, whereas TSC2 was not recruited. These results establish a correlation between GSK3 phosphorylation and its colocalization with APPL1 and Akt. To further investigate the functional importance of the endosomal localization of Appl1 for Akt activation in zebrafish, the authors tested whether mutant Appl1 proteins that localize to other cellular compartments could rescue the apoptosis induced by knockdown of endogenous Appl1. The authors found that only endosomal Appl1 supports Akt activation and promotes cell survival; neither nuclear nor soluble Appl1 proteins could rescue apoptosis induced by the knockdown of Appl1. These observations reveal an exciting model in which Appl1 regulates Akt substrate selectivity, possibly by recruiting Akt and its substrate Gsk3 to the same subcellular compartment (Figure 1). In addition to spatial regulation, previous studies have indicated a role for signal strength in Akt substrate selectivity. The mammalian target of rapamycin complex 2 (mTORC2) is responsible for phosphorylation of Akt at serine 473, which increases kinase activity several-fold (Sarbassov et al., 2005Sarbassov D.D. Guertin D.A. Ali S.M. Sabatini D.M. Science. 2005; 307: 1098-1101Crossref PubMed Scopus (4870) Google Scholar). Genetic deletion of Sin1 (an essential subunit of mTORC2) in mice abolishes serine 473 phosphorylation but has little effect on phosphorylation of threonine 308 in Akt's activation loop. Interestingly, cells lacking Sin1 display a severe defect in the phosphorylation of Foxo1, whereas the effect on Gsk3 and Tsc2 phosphorylation is minor (Jacinto et al., 2006Jacinto E. Facchinetti V. Liu D. Soto N. Wei S. Jung S.Y. Huang Q. Qin J. Su B. Cell. 2006; 127: 125-137Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar). This suggests that full activation of Akt is required for the phosphorylation of some but not all Akt substrates. Together, these studies demonstrate that Akt substrate specificity can be controlled by multiple mechanisms, including signal strength and spatial regulation. The report by Schenck et al. provides new insights into the substrate selectivity of Akt but also raises many important questions regarding Akt signaling and APPL1. How does APPL1 enhance Akt phosphorylation? Does it recruit mTORC2 to the endosome? APPL1 is known to interact with numerous cell-surface receptors, including receptors for nerve growth factor, follicle-stimulating hormone, and adiponectin. Does APPL1 play a general role in dictating signaling specificity of these interacting proteins? If APPL1 mainly contributes to cell survival, it should promote phosphorylation of Akt substrates such as BAD and FOX1 that regulate apoptosis but not the phosphorylation of substrates that regulate proliferation, such as p27. Future work may also reveal mechanisms other than spatial regulation and signal strength that contribute to the signaling specificity of Akt. The Endosomal Protein Appl1 Mediates Akt Substrate Specificity and Cell Survival in Vertebrate DevelopmentSchenck et al.CellMay 02, 2008In BriefDuring development of multicellular organisms, cells respond to extracellular cues through nonlinear signal transduction cascades whose principal components have been identified. Nevertheless, the molecular mechanisms underlying specificity of cellular responses remain poorly understood. Spatial distribution of signaling proteins may contribute to signaling specificity. Here, we tested this hypothesis by investigating the role of the Rab5 effector Appl1, an endosomal protein that interacts with transmembrane receptors and Akt. Full-Text PDF Open Archive" @default.
• W2004993211 created "2016-06-24" @default.
• W2004993211 creator A5000868352 @default.
• W2004993211 creator A5016834516 @default.
• W2004993211 date "2008-05-01" @default.
• W2004993211 modified "2023-10-14" @default.
• W2004993211 title "Substrate Selectivity APPLies to Akt" @default.
• W2004993211 cites W1975510716 @default.
• W2004993211 cites W1984621921 @default.
• W2004993211 cites W2011282245 @default.
• W2004993211 cites W2050624870 @default.
• W2004993211 cites W2058138221 @default.
• W2004993211 cites W2097767970 @default.
• W2004993211 cites W2117028091 @default.
• W2004993211 cites W2137035181 @default.
• W2004993211 cites W4238567307 @default.
• W2004993211 doi "https://doi.org/10.1016/j.cell.2008.04.015" @default.
• W2004993211 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18455980" @default.
• W2004993211 hasPublicationYear "2008" @default.
• W2004993211 type Work @default.
• W2004993211 sameAs 2004993211 @default.
• W2004993211 citedByCount "5" @default.
• W2004993211 countsByYear W20049932112015 @default.
• W2004993211 countsByYear W20049932112017 @default.
• W2004993211 countsByYear W20049932112020 @default.
• W2004993211 crossrefType "journal-article" @default.
• W2004993211 hasAuthorship W2004993211A5000868352 @default.
• W2004993211 hasAuthorship W2004993211A5016834516 @default.
• W2004993211 hasBestOaLocation W20049932111 @default.
• W2004993211 hasConcept C118792377 @default.
• W2004993211 hasConcept C11960822 @default.
• W2004993211 hasConcept C12554922 @default.
• W2004993211 hasConcept C161790260 @default.
• W2004993211 hasConcept C18903297 @default.
• W2004993211 hasConcept C2777289219 @default.
• W2004993211 hasConcept C55493867 @default.
• W2004993211 hasConcept C75217442 @default.
• W2004993211 hasConcept C86803240 @default.
• W2004993211 hasConcept C95444343 @default.
• W2004993211 hasConceptScore W2004993211C118792377 @default.
• W2004993211 hasConceptScore W2004993211C11960822 @default.
• W2004993211 hasConceptScore W2004993211C12554922 @default.
• W2004993211 hasConceptScore W2004993211C161790260 @default.
• W2004993211 hasConceptScore W2004993211C18903297 @default.
• W2004993211 hasConceptScore W2004993211C2777289219 @default.
• W2004993211 hasConceptScore W2004993211C55493867 @default.
• W2004993211 hasConceptScore W2004993211C75217442 @default.
• W2004993211 hasConceptScore W2004993211C86803240 @default.
• W2004993211 hasConceptScore W2004993211C95444343 @default.
• W2004993211 hasIssue "3" @default.
• W2004993211 hasLocation W20049932111 @default.
• W2004993211 hasLocation W20049932112 @default.
• W2004993211 hasOpenAccess W2004993211 @default.
• W2004993211 hasPrimaryLocation W20049932111 @default.
• W2004993211 hasRelatedWork W1534104940 @default.
• W2004993211 hasRelatedWork W1995644121 @default.
• W2004993211 hasRelatedWork W2061953421 @default.
• W2004993211 hasRelatedWork W2076242488 @default.
• W2004993211 hasRelatedWork W2141678026 @default.
• W2004993211 hasRelatedWork W2909023549 @default.
• W2004993211 hasRelatedWork W3158746668 @default.
• W2004993211 hasRelatedWork W3197256149 @default.
• W2004993211 hasRelatedWork W4362602560 @default.
• W2004993211 hasRelatedWork W2059738610 @default.
• W2004993211 hasVolume "133" @default.
• W2004993211 isParatext "false" @default.
• W2004993211 isRetracted "false" @default.
• W2004993211 magId "2004993211" @default.
• W2004993211 workType "article" @default.