Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking

Chamberlain, M. Dean; Oberg, Jennifer C.; Furber, Levi A.; Poland, Sharon Franceska; Hawrysh, Andrea D.; Knafelc, Stacey M.; McBride, Heidi M.; Anderson, Deborah H.

doi:10.1016/j.cellsig.2010.05.025

Cited by 39 publications

(33 citation statements)

References 53 publications

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“…These data are in agreement with earlier studies showing that expression of a GAPdeficient form of p85a e the regulatory subunit of PI3K e leads to transformation of fibroblasts, as shown by anchorage independence and tumorigenicity in vivo [20]. Given that p85a is a GAP for Rab4 and Rab5 [21], expression of a GAP-deficient p85a mutant leads to increased cell proliferation and signaling by growth factors [20,22]. However, these studies did not address the precise role of , harvested and incubated with propidium iodide.…”

Section: Discussionsupporting

confidence: 91%

Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Silva

Soto

Díaz

et al. 2015

Biochemical and Biophysical Research Communications

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Section: Discussionsupporting

confidence: 91%

Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Silva

Soto

Díaz

et al. 2015

Biochemical and Biophysical Research Communications

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“…It was also shown that p85 exhibits in vitro GTPase-activating protein (GAP) activity toward Rab5, which regulates vesicle trafficking and actin remodeling (106, 107). A p85α mutant with defective GAP activities perturbed PDGF receptor trafficking and caused cellular transformation via a kinase-independent mechanism (105, 108). Whether the GAP activity of p85 or Rab5 contributes to IL2Rβ or EpoR endocytosis is unclear.…”

Section: Discussionmentioning

confidence: 99%

Cytokine Receptor Endocytosis: New Kinase Activity-Dependent and -Independent Roles of PI3K

2017

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Type I and II cytokine receptors are cell surface sensors that bind cytokines in the extracellular environment and initiate intracellular signaling to control processes such as hematopoiesis, immune function, and cellular growth and development. One key mechanism that regulates signaling from cytokine receptors is through receptor endocytosis. In this mini-review, we describe recent advances in endocytic regulations of cytokine receptors, focusing on new paradigms by which PI3K controls receptor endocytosis through both kinase activity-dependent and -independent mechanisms. These advances underscore the notion that the p85 regulatory subunit of PI3K has functions beyond regulating PI3K kinase activity, and that PI3K plays both positive and negative roles in receptor signaling. On the one hand, the PI3K/Akt pathway controls various aspects downstream of cytokine receptors. On the other hand, it stimulates receptor endocytosis and downregulation, thus contributing to signaling attenuation.

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“…The fact that many RTKs undergo ligand-stimulated internalization and recycling through endosomes, while remaining competent to signal (27–31) suggested to us that RAB35 may function in this process. In considering this possibility, we noted highly elevated levels of tyrosine phosphorylation of the platelet-derived growth factor receptor (PDGFRα/β)—but not of IGF1R, FGFR, VEGFR or MET—in cells expressing the constitutively active RAB35 Q67L allele (Figs.…”

mentioning

confidence: 96%

Identification of an oncogenic RAB protein

Wheeler

Zoncu

Root

et al. 2015

Science

110

120

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In an shRNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small GTPase—a protein previously implicated in endomembrane trafficking—as a new regulator of the PI3K pathway. Depletion of RAB35 suppresses AKT phosphorylation in response to growth factors, whereas expression of a dominant active GTPase-deficient mutant of RAB35 constitutively activates the PI3K/AKT pathway. RAB35 functions downstream of growth factor receptors and upstream of PDK1 and mTORC2 and co-purifies with PI3K in immunoprecipitation assays. Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. Furthermore, oncogenic RAB35 is sufficient to drive PDGFRα to LAMP2-positive endomembranes in the absence of ligand, suggesting there may be latent oncogenic potential in dysregulated endomembrane trafficking.

show abstract

Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking

Cited by 39 publications

References 53 publications

Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Cytokine Receptor Endocytosis: New Kinase Activity-Dependent and -Independent Roles of PI3K

Identification of an oncogenic RAB protein

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