INPP4B Promotes PI3Kα-dependent Late Endosome Formation and Wnt/β-catenin Signaling in Breast Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 26

PMID 34035258

Citations 23

Authors

Samuel J Rodgers

Lisa M Ooms

Viola M J Oorschot

Ralf B Schittenhelm

Elizabeth V Nguyen

Sabryn A Hamila

Natalie Rynkiewicz

Rajendra Gurung

Matthew J Eramo

Absorn Sriratana

Clare G Fedele

Franco Caramia

Sherene Loi

Genevieve Kerr

Helen E Abud

Georg Ramm

Antonella Papa

Andrew M Ellisdon

Roger J Daly

Catriona A McLean

Christina A Mitchell

Affiliations

Soon will be listed here.

Abstract

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER breast cancer via PI(3,4)P to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

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References

Taelman V, Dobrowolski R, Plouhinec J, Fuentealba L, Vorwald P, Gumper I . Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell. 2010; 143(7):1136-48. PMC: 3022472. DOI: 10.1016/j.cell.2010.11.034. View

Gewinner C, Wang Z, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D . Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009; 16(2):115-25. PMC: 2957372. DOI: 10.1016/j.ccr.2009.06.006. View

Toyoshima M, Tanaka N, Aoki J, Tanaka Y, Murata K, Kyuuma M . Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs: its regulatory role on E-cadherin and beta-catenin. Cancer Res. 2007; 67(11):5162-71. DOI: 10.1158/0008-5472.CAN-06-2756. View

Bruderer R, Bernhardt O, Gandhi T, Miladinovic S, Cheng L, Messner S . Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol Cell Proteomics. 2015; 14(5):1400-10. PMC: 4424408. DOI: 10.1074/mcp.M114.044305. View

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View

Futter C, Collinson L, Backer J, Hopkins C . Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J Cell Biol. 2002; 155(7):1251-64. PMC: 2199316. DOI: 10.1083/jcb.200108152. View

Cruciat C, Ohkawara B, Acebron S, Karaulanov E, Reinhard C, Ingelfinger D . Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 2010; 327(5964):459-63. DOI: 10.1126/science.1179802. View

Liu H, Paddock M, Wang H, Murphy C, Geck R, Navarro A . The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer. Cancer Discov. 2020; 10(8):1226-1239. PMC: 7415683. DOI: 10.1158/2159-8290.CD-19-1262. View

Bissig C, Gruenberg J . Lipid sorting and multivesicular endosome biogenesis. Cold Spring Harb Perspect Biol. 2013; 5(10):a016816. PMC: 3783046. DOI: 10.1101/cshperspect.a016816. View

10.

Yuan W, Stawiski E, Janakiraman V, Chan E, Durinck S, Edgar K . Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene. 2012; 32(3):318-26. PMC: 3550595. DOI: 10.1038/onc.2012.53. View

11.

Hopkins B, Pauli C, Du X, Wang D, Li X, Wu D . Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018; 560(7719):499-503. PMC: 6197057. DOI: 10.1038/s41586-018-0343-4. View

12.

Ivetac I, Munday A, Kisseleva M, Zhang X, Luff S, Tiganis T . The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane. Mol Biol Cell. 2005; 16(5):2218-33. PMC: 1087230. DOI: 10.1091/mbc.e04-09-0799. View

13.

Ng S, Mahmoudi T, Danenberg E, Bejaoui I, de Lau W, Korswagen H . Phosphatidylinositol 3-kinase signaling does not activate the wnt cascade. J Biol Chem. 2009; 284(51):35308-13. PMC: 2790960. DOI: 10.1074/jbc.M109.078261. View

14.

Guo S, Chi M, Yang R, Guo X, Zan L, Wang C . INPP4B is an oncogenic regulator in human colon cancer. Oncogene. 2015; 35(23):3049-61. PMC: 4908438. DOI: 10.1038/onc.2015.361. View

15.

Vanlandingham P, Ceresa B . Rab7 regulates late endocytic trafficking downstream of multivesicular body biogenesis and cargo sequestration. J Biol Chem. 2009; 284(18):12110-24. PMC: 2673280. DOI: 10.1074/jbc.M809277200. View

16.

Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo H . Alpelisib for -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019; 380(20):1929-1940. DOI: 10.1056/NEJMoa1813904. View

17.

Tikoo A, Roh V, Montgomery K, Ivetac I, Waring P, Pelzer R . Physiological levels of Pik3ca(H1047R) mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERα-positive tumors. PLoS One. 2012; 7(5):e36924. PMC: 3364244. DOI: 10.1371/journal.pone.0036924. View

18.

Dzneladze I, He R, Woolley J, Son M, Sharobim M, Greenberg S . INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. Leukemia. 2015; 29(7):1485-95. DOI: 10.1038/leu.2015.51. View

19.

Gurung R, Tan A, Ooms L, McGrath M, Huysmans R, Munday A . Identification of a novel domain in two mammalian inositol-polyphosphate 5-phosphatases that mediates membrane ruffle localization. The inositol 5-phosphatase skip localizes to the endoplasmic reticulum and translocates to membrane ruffles following.... J Biol Chem. 2003; 278(13):11376-85. DOI: 10.1074/jbc.M209991200. View

20.

Baryawno N, Sveinbjornsson B, Eksborg S, Chen C, Kogner P, Johnsen J . Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res. 2009; 70(1):266-76. DOI: 10.1158/0008-5472.CAN-09-0578. View