The Hidden Conundrum of Phosphoinositide Signaling in Cancer

Abstract

Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P₃ from PI(4,5)P₂ and the subsequent activation of Akt and its downstream signaling cascades (e.g. mTORC1) dominates the landscape of phosphoinositide signaling axis in cancer research. However, PI(4,5)P₂ is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC), and is now an established lipid messenger pivotal for different cellular events in cancer. Here, we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P₂ and its generating enzymes, the phosphatidylinositol phosphate (PIP) kinases (PIPKs). We highlighted how PI(4,5)P₂ and PIP kinases serve as a proximal node in phosphoinositide signaling axis and how its interaction with cytoskeletal proteins regulates migratory and invasive nexus of metastasizing tumor cells.

Keywords: Akt; PI(3,4,5)P3; PI(4,5)P2; PI3K; PIPKIγ.

Figure 1. Collective Role of PI(4,5)P₂ and PI(3,4,5)P₃ Lipid Messengers and Phosphoinositide Kinases in Cancer Progression

PI(4,5)P₂, PIPKs, and PI(4,5)P₂ effectors regulate different cellular functions, including cytoskeletal reorganization, cell migration, invasion, and basic cellular functioning. PIP(4,5)P₂ is predominantly synthesized by type I PIP kinases (PIPKIα, PIPKIβ and PIPKIγ) and it functions as a substrate of PI3K for PI(3,4,5)P₃ generation downstream of activated receptors. PI(3,4,5)P₃ generation and activation of Akt/mTORC1 is critical for cell growth, survival, metabolism and inhibition of the repertoire of proteins involved in cell apoptosis. Different cellular events involved in cancer progression is collectively regulated by PI(4,5)P₂ and PI(3,4,5)P₃ lipid messengers together with their generating enzymes. GPCR, G-protein coupled receptor; RTK, receptor tyrosine kinase.

Figure 2. PIPKIγ Assembly with Activated Receptor Tyrosine Kinases and Adhesion Receptors for PI(4,5)P₂ Synthesis and PI3K/Akt Activation

PIPKIγ recruitment to activated integrins at the adhesion complex and activated receptor tyrosine kinases (RTKs) may provide the mechanism for de novo synthesis of PI(4,5)P₂ for PI(3,4,5)P₃ generation and Akt activation. PIPKIγ interaction with talin provides selective advantage for PIPKIγ among other PIPKI isoforms to be recruited at the vicinity of activated integrins upon cell stimulation with extracellular matrix proteins. Similarly, interaction with Src promotes PIPKIγ recruitment to activated RTKs for PI(4,5)P₂ and PI(3,4,5)P₃ generation and Akt activation.

Figure 3. Distinct Roles of PIPKI and PIPKII in Cancer Progression

As PIPKI is predominantly involved in PI(4,5)P₂ generation, its role in cancer is coupled with PI(3,4,5)P₃ generation and Akt activation. PI(4,5)P₂ and its effectors, along with PI(3,4,5)P₃, activated Akt and its downstream effector molecules, control various cellular functions, including cell survival, cell growth, apoptosis inhibition, and cytoskeletal reorganization, all of which are required for cancer progression. PIPKII function in cancer is associated with balancing the metabolic stress. The loss of tumor suppressor or oncogenic insults results in increased PI5P generation which is then converted into PI(4,5)P₂ by PIPKII for stress alleviation. In the absence of PIPKII, increased accumulation of PI5P promotes cell senescence.

Figure 4. PIPKIγ Plays Key Role in Epithelial Polarity, Reorganization of Actin Cytoskeleton and Formation of Adhesion Complexes

PIPKIγ, in association with polarized vesicle trafficking complex (AP1B and exocyst), controls E-cadherin trafficking to adherens junctions in polarized epithelial cells. However, in malignant cells, which have lost cell polarity, PIPKIγ and PI(4,5)P₂ play pivotal roles in controlling cytoskeletal reorganization and adhesion complexes, which are key for migrating and invading tumor cells.

Figure I. PIP kinases synthesizing PI(4,5)P₂ in mammalian cells

PI(4,5)P₂ in mammalian cells is primarily synthesized through phosphorylation of the fifth hydroxyl group on the inositol ring of PI(4)P (predominant substrate) by type I PIP kinases (PIPKI) of which there are three genes, PIPKIα, PIPKIβ and PIPKIγ. Type II PIP kinases (PIPKII) synthesize PI(4,5)P₂ by phosphorylating the fourth hydroxyl group of PI(5)P (minor substrate) which is increased by metabolic stress or oncogene expression. PIPKII is also further classified into PIPKIIα, PIPKIIβ and PIPKIIγ. PIPKIγ is the most complex isoform of PIPKI and displays various post-transcriptional splicing variants differing in their C-tails which specify their interactions with distinct binding partners.