Activation of the Phosphatidylinositol 3-Kinase Vps34 by a G Protein α Subunit at the Endosome

Slessareva, Janna E.; Routt, Sheri M.; Temple, Brenda; Bankaitis, Vytas A.; Dohlman, Henrik G.

doi:10.1016/j.cell.2006.04.045

Cited by 211 publications

(254 citation statements)

References 61 publications

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“…These findings and recent reports demonstrating that the Rim101-mediated pH response and MAPK activation via the G␣ subunit Gpa1 and the PI3K Vps34 signal on endosomes highlight a role for these organelles as prominent platforms from which diverse cues are translated into appropriate physiological effects (31,32). It is possible that the involvement of vesicular trafficking in nuclear translocation in response to diverse stimuli is more general than anticipated.…”

Section: Discussionmentioning

confidence: 57%

Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to-endosome trafficking in Saccharomyces cerevisiae

Puria

Zurita-Martinez

Cárdenas

2008

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

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The yeast Saccharomyces cerevisiae has developed specialized mechanisms that enable growth on suboptimal nitrogen sources. Exposure of yeast cells to poor nitrogen sources or treatment with the Tor kinase inhibitor rapamycin elicits activation of Gln3 and transcription of nitrogen catabolite-repressed (NCR) genes whose products function in scavenging and metabolizing nitrogen. Here, we show that mutations in class C and D Vps components, which mediate Golgi-to-endosome vesicle transport, impair nuclear translocation of Gln3, NCR gene activation, and growth in poor nitrogen sources. In nutrient-replete conditions, a significant fraction of Gln3 is peripherally associated with light membranes and partially colocalizes with Vps10-containing foci. These results reveal a role for Golgi-to-endosome vesicular trafficking in TORC1-controlled nuclear translocation of Gln3 and support a model in which Tor-mediated signaling in response to nutrient cues occurs in these compartments. These findings have important implications for nutrient sensing and growth control via mTor pathways in metazoans.rapamycin action ͉ Tor signaling

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Section: Discussionmentioning

confidence: 57%

Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to-endosome trafficking in Saccharomyces cerevisiae

Puria

Zurita-Martinez

Cárdenas

2008

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

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“…Initially demonstrated for arrestin-dependent MAP kinase pathways (30)(31)(32)(33), endosomal signaling via heterotrimeric G proteins has been shown in yeast (34) and recently extended to GPCRs in vertebrates. Sustained cAMP and G S signaling by receptor internalization in early endosomes was originally reported in 2009 for two distinct GPCRs, the thyroid-stimulating hormone receptor (TSHR) (35) and PTHR (2), and recently expanded to the dopamine D1 receptor (D1R) (36).…”

Section: Discussionmentioning

confidence: 99%

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

Wehbi

Stevenson

Feinstein³

et al. 2013

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

153

107

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G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G S )-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G S activation and increases the steady-state levels of activated G S , leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.

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“…Because the retromer complex binds a sorting signal in the Vps10p cytosolic domain (Nothwehr et al, 2000) and contains functionally important PX domains that bind PI3P at the MVB (Burda et al, 2002;Seaman, 2005), this cluster may correspond to a pathway relevant for retromer function. The remaining two PI3 kinase subunits, Vps15p and Vps34p, formed a distinct cluster with p ϭ 1.10 ϫ 10 Ϫ84 , which could reflect their role in creating additional cellular pools of PI3P (Slessareva et al, 2006).…”

Section: Identification Of New and Known Complexesmentioning

confidence: 99%

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Schluter

Lam

Brumm

et al. 2008

MBoC

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Endosomal transport is critical for cellular processes ranging from receptor down-regulation and retroviral budding to the immune response. A full understanding of endosome sorting requires a comprehensive picture of the multiprotein complexes that orchestrate vesicle formation and fusion. Here, we use unsupervised, large-scale phenotypic analysis and a novel computational approach for the global identification of endosomal transport factors. This technique effectively identifies components of known and novel protein assemblies. We report the characterization of a previously undescribed endosome sorting complex that contains two well-conserved proteins with four predicted membrane-spanning domains. Vps55p and Vps68p form a complex that acts with or downstream of ESCRT function to regulate endosomal trafficking. Loss of Vps68p disrupts recycling to the TGN as well as onward trafficking to the vacuole without preventing the formation of lumenal vesicles within the MVB. Our results suggest the Vps55/68 complex mediates a novel, conserved step in the endosomal maturation process. INTRODUCTIONEndosomal protein sorting is a highly conserved cellular process that is required for receptor down-regulation, viral replication, and development (Katzmann et al., 2002;Morita and Sundquist, 2004). Much progress has been made in recent years in identifying distinct multiprotein complexes that regulate the fusion of primary endocytic vesicles, the maturation of an early endosome into a multivesicular body (MVB), and the recycling of proteins and lipids to other organelles (Gruenberg and Stenmark, 2004;Bonifacino and Rojas, 2006). The ESCRT-I, -II, and -III complexes (endosomal-sorting complex required for transport), which act in sequence to regulate the formation of internal vesicles at the MVB, play a central role in endosome biogenesis (Katzmann et al., 2002;Hurley and Emr, 2006). Other transport complexes regulate the targeting and fusion of endosomes or endosome-derived vesicles with other organelles (Bowers and Stevens, 2005;Bonifacino and Rojas, 2006).Many components of the endosomal-sorting machinery were first identified in yeast genetic screens for mutants that are defective in protein transport to the yeast vacuole, which requires functional endosomal sorting and recycling (Bowers and Stevens, 2005). Most of these components have a conserved role in endosome biogenesis in higher cells. Mammalian homologues have been identified for most if not all yeast ESCRT subunits (von Schwedler et al., 2003;Hurley and Emr, 2006), and at least some of the machinery that regulates recycling from the MVB is also well conserved. For example, the five-subunit retromer complex that mediates endosome-to-trans-Golgi network (TGN) transport in yeast is associated with tubular regions of the endosome in mammalian cells and mediates retrograde transport (Arighi et al., 2004;Seaman, 2004). In the past 20 years, classical genetic screens have identified more than 50 vacuole protein-sorting (VPS) genes (Bowers and Stevens, 2005). Surprisingly, ...

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Activation of the Phosphatidylinositol 3-Kinase Vps34 by a G Protein α Subunit at the Endosome

Cited by 211 publications

References 61 publications

Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to-endosome trafficking in Saccharomyces cerevisiae

Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to-endosome trafficking in Saccharomyces cerevisiae

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

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