Isoform-specific Regulation of Akt Signaling by the Endosomal Protein WDFY2

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Mar 2

PMID 20189988

Citations 21

Authors

Helena A Walz

Xiarong Shi

My Chouinard

Catherine A Bue

Deanna M Navaroli

Akira Hayakawa

Qiong L Zhou

Jonathan Nadler

Deborah M Leonard

Silvia Corvera

Affiliations

Soon will be listed here.

Abstract

Recent work has led to the identification of novel endocytic compartments with functional roles in both protein trafficking and growth factor signal transduction. The phosphatidylinositol 3-phosphate binding, FYVE domain-containing protein WDFY2 is localized to a distinct subset of early endosomes, which are localized close to the plasma membrane. Here, we find that the serine/threonine kinase Akt interacts with these endosomes in an isoform-specific manner. Using quantitative fluorescence microscopy we demonstrate specific co-localization of WDFY2 with endogenous Akt2, but not Akt1. Moreover, depletion of WDFY2 leads to impaired phosphorylation of Akt in response to insulin due to isoform specific reduction of Akt2, but not Akt1, protein levels, and to a marked reduction in the insulin-stimulated phosphorylation of numerous Akt substrates. This is accompanied by an impairment in insulin-stimulated glucose transport and, after prolonged silencing, a reduction in the level of expression of adipogenic genes. We propose that WDFY2-enriched endosomes serve as a scaffold that enables specificity of insulin signaling through Akt2.

Citing Articles

Endosomal trafficking protein TBC-2 modulates stress resistance and lifespan through DAF-16-dependent and independent mechanisms.

Traa A, Soo S, AlOkda A, Ko B, Rocheleau C, Van Raamsdonk J Aging Cell. 2023; 22(3):e13762.

PMID: 36794357 PMC: 10014066. DOI: 10.1111/acel.13762.

The Rab GTPase activating protein TBC-2 regulates endosomal localization of DAF-16 FOXO and lifespan.

Meras I, Chotard L, Liontis T, Ratemi Z, Wiles B, Seo J PLoS Genet. 2022; 18(8):e1010328.

PMID: 35913999 PMC: 9371356. DOI: 10.1371/journal.pgen.1010328.

Keratin 8/18 Regulate the Akt Signaling Pathway.

Lim Y, Kim S, Yoon H, Ku N Int J Mol Sci. 2021; 22(17).

PMID: 34502133 PMC: 8430995. DOI: 10.3390/ijms22179227.

Fusion genes in gynecologic tumors: the occurrence, molecular mechanism and prospect for therapy.

Lu B, Jiang R, Xie B, Wu W, Zhao Y Cell Death Dis. 2021; 12(8):783.

PMID: 34381020 PMC: 8357806. DOI: 10.1038/s41419-021-04065-0.

P63 modulates the expression of the WDFY2 gene which is implicated in cancer regulation and limb development.

Monti P, Ciribilli Y, Foggetti G, Menichini P, Bisio A, Cappato S Biosci Rep. 2019; 39(12).

PMID: 31789342 PMC: 6914664. DOI: 10.1042/BSR20192114.

References

Hayakawa A, Leonard D, Murphy S, Hayes S, Soto M, Fogarty K . The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis. Proc Natl Acad Sci U S A. 2006; 103(32):11928-33. PMC: 1567675. DOI: 10.1073/pnas.0508832103. View

Miaczynska M, Christoforidis S, Giner A, Shevchenko A, Uttenweiler-Joseph S, Habermann B . APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell. 2004; 116(3):445-56. DOI: 10.1016/s0092-8674(04)00117-5. View

Raiborg C, Bache K, Mehlum A, Stenmark H . Function of Hrs in endocytic trafficking and signalling. Biochem Soc Trans. 2001; 29(Pt 4):472-5. DOI: 10.1042/bst0290472. View

Hanada M, Feng J, Hemmings B . Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta. 2004; 1697(1-2):3-16. DOI: 10.1016/j.bbapap.2003.11.009. View

Saito T, Jones C, Huang S, Czech M, Pilch P . The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007; 282(44):32280-7. DOI: 10.1074/jbc.M704150200. View

Lindmo K, Stenmark H . Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci. 2006; 119(Pt 4):605-14. DOI: 10.1242/jcs.02855. View

Mosesson Y, Mills G, Yarden Y . Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer. 2008; 8(11):835-50. DOI: 10.1038/nrc2521. View

von Zastrow M . Role of endocytosis in signalling and regulation of G-protein-coupled receptors. Biochem Soc Trans. 2001; 29(Pt 4):500-4. DOI: 10.1042/bst0290500. View

Cho H, Thorvaldsen J, Chu Q, Feng F, Birnbaum M . Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 2001; 276(42):38349-52. DOI: 10.1074/jbc.C100462200. View

10.

Leonard D, Hayakawa A, Lawe D, Lambright D, Bellve K, Standley C . Sorting of EGF and transferrin at the plasma membrane and by cargo-specific signaling to EEA1-enriched endosomes. J Cell Sci. 2008; 121(Pt 20):3445-58. PMC: 2586290. DOI: 10.1242/jcs.031484. View

11.

Yan D, Guo L, Wang Y . Requirement of dendritic Akt degradation by the ubiquitin-proteasome system for neuronal polarity. J Cell Biol. 2006; 174(3):415-24. PMC: 2064237. DOI: 10.1083/jcb.200511028. View

12.

Fritzius T, Frey A, Schweneker M, Mayer D, Moelling K . WD-repeat-propeller-FYVE protein, ProF, binds VAMP2 and protein kinase Czeta. FEBS J. 2007; 274(6):1552-66. DOI: 10.1111/j.1742-4658.2007.05702.x. View

13.

Zoncu R, Perera R, Balkin D, Pirruccello M, Toomre D, De Camilli P . A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell. 2009; 136(6):1110-21. PMC: 2705806. DOI: 10.1016/j.cell.2009.01.032. View

14.

Xiang T, Ohashi A, Huang Y, Pandita T, Ludwig T, Powell S . Negative Regulation of AKT Activation by BRCA1. Cancer Res. 2008; 68(24):10040-4. PMC: 2605656. DOI: 10.1158/0008-5472.CAN-08-3009. View

15.

Cho H, Mu J, Kim J, Thorvaldsen J, Chu Q, Crenshaw 3rd E . Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001; 292(5522):1728-31. DOI: 10.1126/science.292.5522.1728. View

16.

Di Guglielmo G, Le Roy C, Goodfellow A, Wrana J . Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003; 5(5):410-21. DOI: 10.1038/ncb975. View

17.

Easton R, Cho H, Roovers K, Shineman D, Mizrahi M, Forman M . Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 2005; 25(5):1869-78. PMC: 549378. DOI: 10.1128/MCB.25.5.1869-1878.2005. View

18.

Medina E, Afsari R, Ravid T, Castillo S, Erickson K, Goldkorn T . Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. Endocrinology. 2005; 146(6):2726-35. DOI: 10.1210/en.2004-1074. View

19.

Bellve K, Leonard D, Standley C, Lifshitz L, Tuft R, Hayakawa A . Plasma membrane domains specialized for clathrin-mediated endocytosis in primary cells. J Biol Chem. 2006; 281(23):16139-46. DOI: 10.1074/jbc.M511370200. View

20.

Fritzius T, Moelling K . Akt- and Foxo1-interacting WD-repeat-FYVE protein promotes adipogenesis. EMBO J. 2008; 27(9):1399-410. PMC: 2374844. DOI: 10.1038/emboj.2008.67. View