PI3K isoforms in cell signalling and vesicle trafficking

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids which directly activate signal transduction pathways. In addition to being frequently genetically-activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder which predisposes to lymphoma. The class II and III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an indirect impact on cell signalling. Here we summarize current knowledge on the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are stimulated. Areas covered include emerging evidence for isoform-specific regulation and function of Akt family members, potential non-cytotoxic actions of PI3K inhibitors in cancer and regulation of mTORC1 by class II and III PI3Ks. A deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes, and ultimately, in human disease. The cDNA cloning of the first catalytic subunit of a PI3K (p110, Ref. 1) in 1992 revealed close sequence similarity to the Saccharomyces cerevisiae Vps34 gene product, which was soon thereafter documented to possess PI3K activity in that it could convert phosphatidylinositol (PI) to its 3phosphorylated PI(3)P derivative 2. Subsequent bioinformatic and molecular biology approaches based on sequence homology of the kinase domain of these enzymes allowed the isolation of multiple PI3K genes from a range of organisms, with the Waterfield group proposing the now generally-accepted classification of the isoforms of PI3K 3-6. The main role of Vps34 in yeast in regulating the transport of proteins to the lysosome-like vacuole 7 indicates that regulation of vesicular traffic is the most ancient function of 3-phosphoinositides, with a role in signalling being a later addition in eukaryotic evolution 8. Genetic and pharmacological approaches have now uncovered the broad functions of the different PI3K isoforms, some of which are targets of the first approved PI3K inhibitors for the treatment of human cancer. The challenges faced in effectively targeting PI3K in disease have illustrated that much remains to be learned about PI3K biology. In this review, we summarize key recent insights into PI3K signalling and cell biology in mammals, for example, newly discovered human syndromes, resulting from constitutive activation of class I PI3Ks leading to tissue overgrowth 9 or immune deregulation 10, 11. Despite having been discovered over two decades ago 12, 13 , the class II PI3Ks remain the most enigmatic PI3K subfamily. Recent studies have started to uncover mechanisms by which these PI3Ks are regulated and how t...

NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells

“…PI3K activation is best known for promoting cell survival, glucose uptake, anabolic metabolism, cell proliferation and cell migration ( 1 ). Among the class IA PI3K isoforms (PI3Kα, PI3Kβ, PI3Kδ), the ubiquitously-expressed PI3Kα, encoded by the PIK3CA gene in humans, is the main regulator of organismal growth, development and survival ( 2 ).…”

PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation

“…The pAKT response to EGF is more rapid than the pERK response, peaking at about 3 min (Zheng et al, 2013), which likely explains why significant changes in AKT activation in response to ligands at 5 and 60 min as for pERK ( Figures 5-7) were difficult to detect using flow cytometry methods used here. PI3K and AKT signaling are important for coordinating proliferative growth factor signaling and metabolism (Bilanges et al, 2019;Manning and Toker, 2017), yet it may be that only low levels of AKT activity are required for neuronal differentiation. Nevertheless, given the interconnected nature of cell signaling pathways (Grimes et al, 2018;Zheng et al, 2013), we can predict coordination with other signaling pathways downstream of RTK activation during differentiation, such as PLC-g, PI3K, AKT, and mTOR complexes, which are also involved in endocytic trafficking and lysosomal degradation (Bilanges et al, 2019;Manning and Toker, 2017).…”

“…PI3K and AKT signaling are important for coordinating proliferative growth factor signaling and metabolism (Bilanges et al, 2019;Manning and Toker, 2017), yet it may be that only low levels of AKT activity are required for neuronal differentiation. Nevertheless, given the interconnected nature of cell signaling pathways (Grimes et al, 2018;Zheng et al, 2013), we can predict coordination with other signaling pathways downstream of RTK activation during differentiation, such as PLC-g, PI3K, AKT, and mTOR complexes, which are also involved in endocytic trafficking and lysosomal degradation (Bilanges et al, 2019;Manning and Toker, 2017). In any case, our results support a role for SFKs, namely FYN and LYN, and control of their activity and intracellular localization by PAG1, as a mechanism to distinguish differentiation signals caused by the RTKs TRKA and RET.…”

Myo‐inositol in health and disease: its impact on semen parameters and male fertility

“…With other osmolytes, all called ‘chemical chaperones’, MI also stabilizes and rescues misfolded proteins (Thurson et al , ; Garcia‐Perez & Burg, ; Gullans & Verbalis, ; Welch & Brown, ; Yancey, ). In addition to these functions, MI and its derivatives are involved in numerous biological processes, including protein tethering to the cell surface, cell signaling and vesicle trafficking, membrane excitability, regulation of ion channel opening, intracellular calcium signaling, cytoskeleton and chromatin dynamics and remodeling, gene expression, and epigenome regulation (Hammond et al , ; Roest et al , ; Bevilacqua & Bizzarri, ; Uličná et al , ; Bilanges et al , ). Consequently, alterations in MI transport and metabolism have been found associated with numerous pathological conditions, including metabolic syndrome, type 2 diabetes and gestational diabetes, thyroid dysfunctions, polycystic ovarian syndrome and other gynecological disorders, abnormalities in gamete production, fertilization and embryonic development, Down’s syndrome, psychiatric disorders (i.e., depression, panic disorders, obsessive compulsive disorder), Alzheimer’s disease, preterm broncho‐pulmonary diseases (including respiratory distress syndrome and retinopathy of prematurity), liver and intestinal steatosis, and cancer.…”