Class IA PI3K isoforms lead to differential signalling downstream of PKB/Akt
Author:
Catalak Yilmaz Hazal B.1ORCID, Sulaiman Mahnoor1ORCID, Isik Ozlem Aybuke1ORCID, Cizmecioglu Onur1ORCID
Affiliation:
1. Department of Molecular Biology and Genetics , Ihsan Dogramaci Bilkent University , Ankara , Türkiye
Abstract
Abstract
Objectives
The catalytic subunits of Class IA PI3K, p110α, p110β, and p110δ, phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the plasma membrane. In cancer, these catalytic subunits are usually found to be altered or amplified. Because pan-PI3K inhibition results in systemic toxicities, finding specific targets for the ubiquitous PI3K isoforms offers considerable potential for enhancing the effectiveness of PI3K-targeted therapy.
Methods
We aim to delineate the isoform-specific druggable targets of the PI3K by deleting PIK3CA (encoding p110α) and PIK3CB (encoding p110β) by Cre mediated excision and ectopically expressing p110α, p110β, or p110δ with or without myristoylation (Myr) tag in mouse embryonic fibroblasts (MEFs). Myr is a lipidation signal that translocates proteins to plasma membrane permanently. This translocation renders p110s constitutively activated as they remain in close proximity to PIP2 on the membrane.
Results
Unique and redundant Akt targets are identified downstream of different PI3K isoforms. mTORC1, one of the targets of fully-activated Akt, has been observed to be differentially regulated in MEFs upon expression of p110α or p110β. The varying dependencies on mTORC1 and Rac1 led us to analyse a potential scaffolding function of p110β with Rac1 to mediate phosphorylation and activation of mTOR using platforms for the modeling of biomolecular complexes. We also documented that p110α and p110β support cell cycle kinetics differentially.
Conclusions
This study suggests differential regulation of protein translation, metabolism, cell cycle, and survival signaling downstream of unique p110 targets, underlying the importance of cancer treatment according to the deregulated p110 isoform.
Publisher
Walter de Gruyter GmbH
Subject
Biochemistry (medical),Clinical Biochemistry,Molecular Biology,Biochemistry
Reference39 articles.
1. Rommel, C, Vanhaesebroeck, B, Vogt, PK. Phosphoinositide 3-kinase in health and disease. London: Springer; 2010:267–78 pp. 2. Wozniak, DJ, Kajdacsy-Balla, A, Macias, V, Ball-Kell, S, Zenner, ML, Bie, W, et al.. PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer. Nat Commun 2017;8, https://doi.org/10.1038/s41467-017-01574-5, 3. Sueta, A, Yamamoto, Y, Yamamoto-Ibusuki, M, Hayashi, M, Takeshita, T, Yamamoto, S, et al.. An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer. PLoS One 2014;9:1–17, https://doi.org/10.1371/journal.pone.0116054. 4. Cizmecioglu, O, Ni, J, Xie, S, Zhao, JJ, Roberts, TM. Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss. Elife 2016;5:1–21, https://doi.org/10.7554/elife.17635. 5. Burke, JE, Williams, RL. Dynamic steps in receptor tyrosine kinase mediated activation of class IA phosphoinositide 3-kinases (PI3K) captured by H/D exchange (HDX-MS). Adv Biol Regul [Internet] 2013;53:97–110, https://doi.org/10.1016/j.jbior.2012.09.005.
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