Interaction and Functional Analyses of Human VPS34/p150 Phosphatidylinositol 3‐Kinase Complex with Rab7

Stein, Mary‐Pat; Cao, Canhong; Tessema, Mathewos; Feng, Yan; Romero, Elsa; Welford, Angela; Wandinger‐Ness, Angela

doi:10.1016/s0076-6879(05)03055-7

Cited by 24 publications

(34 citation statements)

References 40 publications

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“…2C). To ensure that the rescue of OT1-FD T cells by 3-MA was not due to a potential off-target effect, we used retroviral transduction of a dominant-negative form of Vps34 (Vps34-KD) to block autophagic signaling (37). At 2-, 4-, and 6-d postinfection, cultures were harvested and live T cells were assayed for Thy1.1 expression, a marker for the proportion of cells expressing the MiT retrovirus (38).…”

Section: Resultsmentioning

confidence: 99%

FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells

Bell

Leverrier

Weist

et al. 2008

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

276

257

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Fas-associated death domain protein (FADD) and caspase-8 (casp8) are vital intermediaries in apoptotic signaling induced by tumor necrosis factor family ligands. Paradoxically, lymphocytes lacking FADD or casp8 fail to undergo normal clonal expansion following antigen receptor cross-linking and succumb to caspase-independent cell death upon activation. Here we show that T cells lacking FADD or casp8 activity are subject to hyperactive autophagic signaling and subvert a cellular survival mechanism into a potent death process. T cell autophagy, enhanced by mitogenic signaling, recruits casp8 through interaction with FADD:Atg5-Atg12 complexes. Inhibition of autophagic signaling with 3-methyladenine, dominant-negative Vps34, or Atg7 shRNA rescued T cells expressing a dominant-negative FADD protein. The necroptosis inhibitor Nec-1, which blocks receptor interacting protein kinase 1 (RIP kinase 1), also completely rescued T cells lacking FADD or casp8 activity. Thus, while autophagy is necessary for rapid T cell proliferation, our findings suggest that FADD and casp8 form a feedback loop to limit autophagy and prevent this salvage pathway from inducing RIPK1-dependent necroptotic cell death. Thus, linkage of FADD and casp8 to autophagic signaling intermediates is essential for rapid T cell clonal expansion and may normally serve to promote caspase-dependent apoptosis under hyperautophagic conditions, thereby averting necrosis and inflammation in vivo.apoptosis ͉ autophagy ͉ caspases ͉ FADD ͉ necroptosis

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Section: Resultsmentioning

confidence: 99%

FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells

Bell

Leverrier

Weist

et al. 2008

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

276

257

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“…Through an affinity chromatography approach, an unexpected molecular complexity of the regulators and effectors downstream from Rab5 was first revealed (Christoforidis et al 1999 function is the heterodimeric phosphatidylinositol-3-kinase (PI3K) Vps34/Vps15 complex (Christoforidis et al 1999;Murray et al 2002;Stein et al 2003Stein et al , 2005. Originally discovered in yeast as an essential component for vacuolar protein sorting (Schu et al 1993), Vps34 catalyzes the phosphorylation of phosphatidylinositol to yield phosphatidylinositol-3-phosphate (PI3P).…”

Section: Rab Gtpases and Lipid Metabolism In The Control Of Traffickimentioning

confidence: 99%

Rab Proteins and the Compartmentalization of the Endosomal System

Wandinger‐Ness

Zerial

2014

Cold Spring Harbor Perspectives in Biology

510

469

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Of the approximately 70 human Rab GTPases, nearly three-quarters are involved in endocytic trafficking. Significant plasticity in endosomal membrane transport pathways is closely coupled to receptor signaling and Rab GTPase-regulated scaffolds. Here we review current literature pertaining to endocytic Rab GTPase localizations, functions, and coordination with regulatory proteins and effectors. The roles of Rab GTPases in (1) compartmentalization of the endocytic pathway into early, recycling, late, and lysosomal routes; (2) coordination of individual transport steps from vesicle budding to fusion; (3) effector interactomes; and (4) integration of GTPase and signaling cascades are discussed.

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“…Another pathway by which PI3K could suppress lipolysis independently of Akt is through the regulation of lipid droplet trafficking by Rab proteins. PI3 kinases have been proposed to interact with Rab proteins and have been implicated in membrane trafficking (31,53,54,65). The proteomic analysis of lipid droplets has identified associated small GTP-binding proteins such as Rab5 and Rab18 (6).…”

Section: Fig 5 Primary Adipocyte Analysis Demonstratesmentioning

confidence: 99%

Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway

Choi

Tucker

Gross

et al. 2010

Molecular and Cellular Biology

186

135

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After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.

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Interaction and Functional Analyses of Human VPS34/p150 Phosphatidylinositol 3‐Kinase Complex with Rab7

Cited by 24 publications

References 40 publications

FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells

FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells

Rab Proteins and the Compartmentalization of the Endosomal System

Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway

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