title: The lipid kinase PI4KIIIβ is highly expressed in breast tumors and activates Akt in cooperation with Rab11a.
abstract: Emerging evidence now implicates phosphatidylinositol 4-kinases (PI4K), enzymes that generate PI(4)P from phosphatidylinositol (PtdIns), in cancer. In this study, we investigate the role of PI4KIIIβ, one of four mammalian PI4Ks, in breast cancer. Although PI4KIIIβ protein levels are low in normal breast tissue, we find that approximately 20% of primary human breast tumors overexpress it. Expression of PI4KIIIβ in breast carcinoma cells leads to increased Akt activation, dependent on increased PI(3,4,5)P3 production. However, a kinase-inactive version of PI4KIIIβ also led to increased Akt activation, and no changes in PI(4)P or PI(4,5)P2 lipid abundance were detected in the PI4KIIIβ-overexpressing cells. This implies that PI4KIIIβ regulates PI(3,4,5)P3 and Akt independent of PI(4)P production. We find that the PI4KIIIβ-binding protein, Rab11a, a small GTPase that regulates endosomal recycling, is involved in PI4KIIIβ-mediated activation of Akt, as RNAi depletion of Rab11a impairs Akt activation. Furthermore, ectopic PI4KIIIβ expression alters cellular Rab11a distribution and enhances recruitment of PI4KIIIβ and Rab11a to recycling endosomes. This work suggests that PI4KIIIβ affects PI3K/Akt signaling through Rab11a and endosomal trafficking, independent of its lipid kinase activity. Thus, PI4KIIIβ likely plays a role in breast oncogenesis and that cooperation between Rab11a and PI4KIIIβ represents a novel Akt activation pathway.
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Anne A
authors: AA
authors: Morrow
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Mohsen Amir
authors: MA
authors: Alipour
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors: Dave
authors: D
authors: Bridges
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors: Zemin
authors: Z
authors: Yao
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
authors: Alan R
authors: AR
authors: Saltiel
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. jlee@uottawa.ca.
authors: Jonathan M
authors: JM
authors: Lee
mesh_terms: D000818:Animals; D055162:Biocatalysis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D007295:Inositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C118500:inositol 3,4,5-trisphosphate; C581087:PI4KB protein, human