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Identification of an oncogenic RAB protein

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Science  09 Oct 2015:
Vol. 350, Issue 6257, pp. 211-217
DOI: 10.1126/science.aaa4903

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Cancer as a case of uncontrolled traffic

Healthy cells are like skilled air traffic controllers. They continually move proteins to and from the cellular destinations where they are needed, usually without mishap, through an elaborate system of endomembranes. Wheeler et al. show that a glitch in the traffic control system can help propel a cell toward malignancy (see the Perspective by Ferguson). RAB35, a protein previously implicated in endomembrane trafficking, is a key regulator of a well-known oncogenic signaling pathway. Mutations in RAB35 found in certain human tumors aberrantly activate this pathway and cause mislocalization of a factor that promotes cell growth.

Science, this issue p. 211, see also p. 162

Abstract

In a short hairpin RNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small guanosine triphosphatase (GTPase)—a protein previously implicated in endomembrane trafficking—as a regulator of the phosphatidylinositol 3′-OH kinase (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 copurifies 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 platelet-derived growth factor receptor α to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.

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