FIP200, a key signaling node to coordinately regulate various cellular processes

Gan, Boyi; Guan, Jun

doi:10.1016/j.cellsig.2007.10.021

Cited by 64 publications

(70 citation statements)

References 56 publications

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“…24 FIP200 associates with many other proteins besides ULK1, including several kinases whose signaling is also affected by FIP200. 26 This suggests that FIP200 affects multiple signaling pathways and may have multiple functions in addition to a role in autophagy. It is possible that both FIP200 and Atg101 are required to fulfill an Atg17-like function in higher eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

“…Known ULK1-interacting proteins include GATE-16, GABARAP, SynGAP, Syntenin, p62/SQSTM1 and FIP200. [22][23][24][25] FIP200, which binds multiple proteins and regulates various cellular functions, 26 is particularly interesting in that it is essential for autophagy, modulates ULK1 activity, and has coiled-coil domains, making FIP200 a potential Atg17 ortholog. 24 Regarding Atg13, a gapped-blast search of fungal, plant and human databases identified the uncharacterized protein FLJ20698 as a potential human ortholog of Atg13.…”

Section: Introductionmentioning

confidence: 99%

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A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

Mercer

Kaliappan²,

Dennis³

2009

Autophagy

376

321

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Macroautophagy is an intracellular, vesicle-mediated mechanism for the sequestration and ultimate lysosomal degradation of cytoplasmic proteins, organelles and macromolecules. The macroautophagy process and many of the autophagy-specific (Atg) proteins are remarkably well conserved in higher eukaryotes. In yeast, the Atg1 kinase complex includes Atg1, Atg13, Atg17, and at least four other interacting proteins, some of which are phosphorylated in a TOR-dependent manner, placing the Atg1 signaling complex downstream of a major nutrient-sensing pathway. Atg1 orthologs, including mammalian unc-51-like kinase 1 (ULK1), have been identified in higher eukaryotes and have been functionally linked to autophagy. This suggests that other components of the Atg1 complex exist in higher eukaryotes. Recently, a putative human Atg13 ortholog, FLJ20698, was identified by gapped-BLAST analysis. We show here that FLJ20698 (Atg13) is a ULK1-interacting phosphoprotein that is essential for macroautophagy. Furthermore, we identify a novel, human Atg13-interacting protein, FLJ11773, which we have termed Atg101. Atg101 is essential for autophagy and interacts with ULK1 in an Atg13-dependent manner. Additionally, we present evidence that intracellular localization of the ULK1 complex is regulated by nutrient conditions. Finally, we demonstrate that Atg101 stabilizes the expression of Atg13 in the cell, suggesting that Atg101 contributes to Atg13 function by protecting Atg13 from proteasomal degradation. Therefore, the identification of the novel protein, Atg101, and the validation of Atg13 and Atg101 as ULK1-interacting proteins, suggests an Atg1 complex is involved in the induction of macroautophagy in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

Mercer

Kaliappan²,

Dennis³

2009

Autophagy

376

321

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“…In this study, we set out to address these important questions using FIP200 as a model, taking advantage of its several well-characterized additional interactions with other cellular proteins besides its role in canonical autophagy (Gan and Guan 2008). We identified residues 582-585 (LQFL) in FIP200, required for its interaction with Atg13 and autophagy function in vitro.…”

mentioning

confidence: 99%

“…These observations indicate that, despite being essential components of the canonical autophagy pathway, Atgs may have distinct nonautophagic roles. Indeed, FIP200 and beclin1 have been shown to interact with other proteins to regulate diverse cellular functions independently of or in addition to their roles in autophagy (Gan and Guan 2008;He and Levine 2010;Liu et al 2011;Boya et al 2013). Moreover, Atg7, which was thought to be exclusively involved in autophagy, has recently been shown to regulate cell cycle and cell death pathways independently of its E1-like enzymatic activity, which is essential for autophagy (Lee et al 2012).…”

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confidence: 99%

Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model

et al. 2016

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Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582-585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo.

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“…RB1CC1/FIP200 is a FAK-family interacting protein of 200 kDa 123 and a component of the autophagy-initiation complex. 124 Conditional deletion of Rb1cc1 in hemo-endothelial precursors in a TEK/Tie2Cre mouse model results in early lethality from severe anemia.…”

Section: Autophagy and Hscsmentioning

confidence: 99%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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FIP200, a key signaling node to coordinately regulate various cellular processes

Cited by 64 publications

References 56 publications

A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model

Mitophagy in hematopoietic stem cells

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