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PI3K signaling

Emilio Hirsch - PI

Main group members

  • Lorenzo Prever PhD student 

  • Ping Zhang PhD student 

  • Roberta Rubino PhD student 

Research activity

Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases crucial for converting phosphatidylinositol lipids into phosphoinositide second messengers. Within this PI3K family, class II PI3Ks emerge as a distinct subgroup actively involved in various cellular signaling pathways. More specifically, class II PI3Ks play a key role in generating two essential second messengers: phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2]. These second messengers exert regulatory control over a diverse array of cellular processes, including cell growth, survival, metabolism, and intracellular trafficking. Class II PI3Ks can be further classified into three subtypes: PI3K-C2α, PI3K-C2β, and PI3K-C2γ. Distinguishing themselves from class I PI3Ks, these class II variants exhibit unique structural characteristics and regulatory mechanisms. Notably, class II PI3Ks feature a distinct domain architecture, comprising a C-terminal phosphoinositide-binding PX (phox homology) domain and an N-terminal unstructured region involved in protein-protein interactions. These structural distinctions play a pivotal role in shaping the functional diversity of class II PI3Ks and determining their specific involvement in cellular processes (see Figure 1).

Figure 1

While the exact functions of class II PI3Ks are still being investigated, extensive research, including studies conducted in our laboratory, has yielded significant insights into their participation in a wide range of cellular processes. Through our investigations, we have elucidated the specific roles of class II PI3K isoforms in various contexts. For instance, our research indicates that PI3K-C2α is not only crucial for mouse embryo development but also plays a vital role in clathrin-dependent endocytosis and vesicle trafficking. We observed that the disruption of PI3K-C2α results in impaired embryonic development and disturbed intracellular transport, underscoring its significance in these processes (Figure 2-3). Additionally, our investigations have uncovered that PI3K-C2α is implicated in the activation of Rab11, a small GTPase that governs intracellular transport and recycling (Figure 3).

Figure 2

These findings provide insights into the regulatory mechanisms mediated by PI3K-C2α in membrane trafficking. Furthermore, our investigations have revealed the significance of PI3K-C2α in the control of cell division, particularly in the context of breast cancer tumorigenesis. We have observed that altered expression or activity of PI3K-C2α impacts cell proliferation and division, suggesting its involvement in the regulation of these processes in cancer cells. Similarly, our studies have concentrated on the role of PI3K-C2β in mitosis progression, specifically in prostate cancer. Through our research, we have clarified the importance of PI3K-C2β in modulating mitotic events and ensuring proper cell division in prostate cancer cells. These findings shed light on the specific functions of PI3K-C2β in the context of cancer biology and provide a potential target for therapeutic interventions. More recently, our investigations have revealed an unexpected role of PI3K-C2β-mediated lipid signaling in the regulation of mTORC1-dependent neuronal excitability. We discovered that PI3K-C2β activity influences neuronal excitability in both mice and humans through its impact on mTORC1 signaling. This discovery highlights the involvement of class II PI3Ks in neuronal function and unveils a novel link between lipid signaling and neuronal excitability. Additionally, our research has clarified the subcellular localization of PI3K-C2γ on early endosomes, offering insights into its compartmentalization within the cell. We have established that PI3K-C2γ is instrumental in regulating Akt2 activation and glycogen storage in the liver. Our studies indicate that the disruption of PI3K-C2γ expression or activity results in the dysregulation of Akt2 signaling, thereby impeding glycogen synthesis and storage in hepatocytes. Collectively, these findings emphasize the varied functions of class II PI3K isoforms and their substantial implications in cellular processes and disease contexts. Ongoing research, including investigations conducted in our laboratory, persists in enhancing our comprehension of the exact mechanisms and signaling pathways governed by class II PI3Ks. This progress lays the groundwork for potential therapeutic interventions and improved clinical outcomes.

Figure 3

Our recent study highlighted the significance of PI(3,4) P2, produced by PI3K-C2α at the midbody during cytokinesis, in ensuring proper cell division at the end of mitosis. The localized production of PI(3,4)P2 plays a critical role in the positioning and activation of the Endosomal Sorting Complex Required for Transport (ESCRT) proteins. These proteins organize essential complexes crucial for cytokinesis, and any dysfunction in ESCRT function during this process can lead to cell refusion and aneuploidy, characterized by an abnormal number of chromosomes. In our examination of breast cancer patients, we observed frequent downregulation of various components of the ESCRT-II/III machinery. This downregulation is associated with increased aneuploidy, suggesting a connection between dysfunctional ESCRT-dependent mechanisms and cell refusion, leading to the development of micronuclei and the leakage of DNA into the cytoplasm. Additionally, we propose that the loss of nuclear membrane repair might further contribute to the presence of cytoplasmic DNA. These processes potentially converge on the activation of the cGAS-STING pathway, involving cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Ultimately, this pathway can promote immune modulation, epithelial-mesenchymal transition (EMT), and cancer progression. In our ongoing projects, we are focused on exploring the interplay between phosphoinositides and ESCRTs in the progression of breast cancer. We aim to address these hypotheses to gain a deeper understanding of the molecular mechanisms underlying cytokinesis and its implications in cancer development. 

  • LEDUCQ TRANSATLANTIC NETWORKS OF EXCELLENCE: Targeting approaches for prevention and treatment of anthracycline-induced cardiotoxicity, GA no. 19CVD02, 2020-2024 

  • AIRC: Understanding the mechanism of action of PI3KC2α in breast cancer progression, IG 21875, 2019-2024 

  • MIUR PRIN: Cellular mechanisms of breast cancer stem cell-driven aggressiveness, GA no. 20177E9EPY, 2018- 2022

  • A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases. Ghigo A, et al., and Hirsch E. Sci Transl Med. 2022 Mar 30;14(638):eabl6328. doi: 10.1126/scitranslmed.abl6328. Epub 2022 Mar 30. 

  • Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer. Li H, et al, andHirsch E. Adv Sci (Weinh). 2022 Mar;9(9):e2103249. doi: 10.1002/advs.202103249. 

  • PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation.  Gulluni F, et al., and Hirsch E. Science. 2021 Dec 10;374(6573):eabk0410. doi: 10.1126/science. abk0410. Epub 2021 Dec 10. 

  • Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Campa CC, et al., and Hirsch E. Nat Commun. 2018 Dec 12;9(1):5232. doi: 10.1038/s41467-018-07698-6. 

  • Rab11 activity and PtdIns(3)P turnover removes recycling cargo from endosomes.  Campa CC, et al., and Hirsch E. Nat Chem Biol. 2018 Aug;14(8):801-810. doi: 10.1038/s41589-018-0086-4. Epub 2018 Jun 18.

  • Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth. Li M, et al., and Ghigo A. Circulation. 2018 Aug 14;138(7):696-711. doi: 10.1161/CIRCULATIONAHA.117.030352. 

  • Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. Gulluni F, et al., and Hirsch E. Cancer Cell. 2017 Oct 9;32(4):444-459.e7. doi: 10.1016/j.ccell.2017.09.002. 

  • PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Franco I, et al., and Hirsch E. Dev Cell. 2014 Mar 31;28(6):647-58. doi: 10.1016/j.devcel.2014.01.022. 

  • PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Patrucco E, et al., and Hirsch E. Cell. 2004 Aug 6;118(3):375-87. doi: 10.1016/j.cell.2004.07.017. 

  • Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Hirsch E, et al., and Wymann MP. Science. 2000 Feb 11;287(5455):1049-53. doi: 10.1126/science.287.5455.104

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