Phosphatidylinositol-3-OH Kinase Signalling is Spatially Organized at Endosomal Compartments by Microtubule-associated Protein 4

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2020 Nov 3

PMID 33139939

Citations 32

Authors

Narendra Thapa

Mo Chen

Hudson T Horn

Suyong Choi

Tianmu Wen

Richard A Anderson

Affiliations

Soon will be listed here.

Abstract

The canonical model of agonist-stimulated phosphatidylinositol-3-OH kinase (PI3K)-Akt signalling proposes that PI3K is activated at the plasma membrane, where receptors are activated and phosphatidylinositol-4,5-bisphosphate is concentrated. Here we show that phosphatidylinositol-3,4,5-trisphosphate generation and activated Akt are instead largely confined to intracellular membranes upon receptor tyrosine kinase activation. Microtubule-associated protein 4 (MAP4) interacts with and controls localization of membrane vesicle-associated PI3Kα to microtubules. The microtubule-binding domain of MAP4 binds directly to the C2 domain of the p110α catalytic subunit. MAP4 controls the interaction of PI3Kα with activated receptors at endosomal compartments along microtubules. Loss of MAP4 results in the loss of PI3Kα targeting and loss of PI3K-Akt signalling downstream of multiple agonists. The MAP4-PI3Kα assembly defines a mechanism for spatial control of agonist-stimulated PI3K-Akt signalling at internal membrane compartments linked to the microtubule network.

Citing Articles

Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation.

Gollowitzer A, Pein H, Rao Z, Waltl L, Bereuter L, Loeser K Nat Commun. 2025; 16(1):1774.

PMID: 40000627 PMC: 11861335. DOI: 10.1038/s41467-025-56711-2.

RIT1 Promotes the Proliferation of Gliomas Through the Regulation of the PI3K/AKT/c-Myc Signalling Pathway.

Liu Z, Jiang H, Kan H, Zhang L, Rao Y, Jiang X J Cell Mol Med. 2025; 29(2):e70362.

PMID: 39833023 PMC: 11745823. DOI: 10.1111/jcmm.70362.

Protective mechanism of safflower yellow injection on myocardial ischemia-reperfusion injury in rats by activating NLRP3 inflammasome.

Li L, Cao C, Guo H, Lin L, Li L, Zhang Y BMC Complement Med Ther. 2025; 25(1):9.

PMID: 39789550 PMC: 11715333. DOI: 10.1186/s12906-025-04747-8.

Asparagine endopeptidase regulates lysosome homeostasis via modulating endomembrane phosphoinositide composition.

Yao L, Zi G, He M, Xu Y, Wang L, Peng B Cell Death Dis. 2025; 15(12):883.

PMID: 39743643 PMC: 11693757. DOI: 10.1038/s41419-024-07187-3.

Linking Phosphoinositides to Proteins: A Novel Signaling PIPeline.

Carrillo N, Awasthi P, Lee J, Wen T, Chen M, Sterling C J Cell Signal. 2024; 5(3):114-121.

PMID: 39582486 PMC: 11584056. DOI: 10.33696/signaling.5.118.

References

Jhawer M, Goel S, Wilson A, Montagna C, Ling Y, Byun D . PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008; 68(6):1953-61. PMC: 3972216. DOI: 10.1158/0008-5472.CAN-07-5659. View

Iqbal K, Liu F, Gong C . Tau and neurodegenerative disease: the story so far. Nat Rev Neurol. 2015; 12(1):15-27. DOI: 10.1038/nrneurol.2015.225. View

Burke J, Williams R . Synergy in activating class I PI3Ks. Trends Biochem Sci. 2015; 40(2):88-100. DOI: 10.1016/j.tibs.2014.12.003. View

Costes S, Daelemans D, Cho E, Dobbin Z, Pavlakis G, Lockett S . Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys J. 2004; 86(6):3993-4003. PMC: 1304300. DOI: 10.1529/biophysj.103.038422. View

Fruman D, Chiu H, Hopkins B, Bagrodia S, Cantley L, Abraham R . The PI3K Pathway in Human Disease. Cell. 2017; 170(4):605-635. PMC: 5726441. DOI: 10.1016/j.cell.2017.07.029. View

Chen M, Choi S, Jung O, Wen T, Baum C, Thapa N . The Specificity of EGF-Stimulated IQGAP1 Scaffold Towards the PI3K-Akt Pathway is Defined by the IQ3 motif. Sci Rep. 2019; 9(1):9126. PMC: 6591252. DOI: 10.1038/s41598-019-45671-5. View

Betz C, Hall M . Where is mTOR and what is it doing there?. J Cell Biol. 2014; 203(4):563-74. PMC: 3840941. DOI: 10.1083/jcb.201306041. View

Thapa N, Choi S, Tan X, Wise T, Anderson R . Phosphatidylinositol Phosphate 5-Kinase Iγ and Phosphoinositide 3-Kinase/Akt Signaling Couple to Promote Oncogenic Growth. J Biol Chem. 2015; 290(30):18843-54. PMC: 4513138. DOI: 10.1074/jbc.M114.596742. View

Thapa N, Horn H, Anderson R . Phosphoinositide spatially free AKT/PKB activation to all membrane compartments. Adv Biol Regul. 2019; 72:1-6. PMC: 6529224. DOI: 10.1016/j.jbior.2019.04.002. View

10.

Chen Y, Kratchmarov R, Lin W, Rothman N, Yen B, Adams W . Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway. Cell Rep. 2018; 22(4):860-868. PMC: 5806629. DOI: 10.1016/j.celrep.2017.12.087. View

11.

Sato M, Ueda Y, Takagi T, Umezawa Y . Production of PtdInsP3 at endomembranes is triggered by receptor endocytosis. Nat Cell Biol. 2003; 5(11):1016-22. DOI: 10.1038/ncb1054. View

12.

Wills R, Goulden B, Hammond G . Genetically encoded lipid biosensors. Mol Biol Cell. 2018; 29(13):1526-1532. PMC: 6080648. DOI: 10.1091/mbc.E17-12-0738. View

13.

Xia X, He C, Wu A, Zhou J, Wu J . Microtubule-Associated Protein 4 Is a Prognostic Factor and Promotes Tumor Progression in Lung Adenocarcinoma. Dis Markers. 2018; 2018:8956072. PMC: 5878896. DOI: 10.1155/2018/8956072. View

14.

Wu H, Shekar S, Flinn R, El-Sibai M, Jaiswal B, Sen K . Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proc Natl Acad Sci U S A. 2009; 106(48):20258-63. PMC: 2787125. DOI: 10.1073/pnas.0902369106. View

15.

Murphy J, Padilla B, Hasdemir B, Cottrell G, Bunnett N . Endosomes: a legitimate platform for the signaling train. Proc Natl Acad Sci U S A. 2009; 106(42):17615-22. PMC: 2764915. DOI: 10.1073/pnas.0906541106. View

16.

Chen M, Wen T, Horn H, Chandrahas V, Thapa N, Choi S . The nuclear phosphoinositide response to stress. Cell Cycle. 2020; 19(3):268-289. PMC: 7028212. DOI: 10.1080/15384101.2019.1711316. View

17.

De Santis M, Gulluni F, Campa C, Martini M, Hirsch E . Targeting PI3K signaling in cancer: Challenges and advances. Biochim Biophys Acta Rev Cancer. 2019; 1871(2):361-366. DOI: 10.1016/j.bbcan.2019.03.003. View

18.

Vadas O, Burke J, Zhang X, Berndt A, Williams R . Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal. 2011; 4(195):re2. DOI: 10.1126/scisignal.2002165. View

19.

Clark A, Toker A . Signalling specificity in the Akt pathway in breast cancer. Biochem Soc Trans. 2014; 42(5):1349-55. DOI: 10.1042/BST20140160. View

20.

Pemberton J, Kim Y, Humpolickova J, Eisenreichova A, Sengupta N, Toth D . Defining the subcellular distribution and metabolic channeling of phosphatidylinositol. J Cell Biol. 2020; 219(3). PMC: 7054996. DOI: 10.1083/jcb.201906130. View