Anti-PIP2 monoclonal antibody, clone 4E23

PIP2 is a cell signaling protein found everywhere: it's stored in the plasma membrane of most eukaryotic cells. A phosphorylated salt of phosphatidylinositol, PIP2 controls many of the cell's most fundamental physiological processes: signaling, cytoskeletal reorganization, membrane protein regulation, and the action of ions. Thus, work on PIP2 offers a basic molecular glimpse into cellular processes and signaling systems. They found, quantified and regulated PIP2 in diseases ranging from cancer to neurodegeneration to cardiovascular disease, and suggested PIP2 as a target. PIP2 is an atom-specific complex made by phosphoryling the 4th and 5th hydroxyl groups of the inositol ring of phosphatidylinositol to bond with proteins. It occupies the cell's wall and acts on various effector molecules to amplify different signaling pathways. PIP2, for example, orchestrates cytoskeletal reorganization through interaction with actin-binding proteins (ERM proteins (Ezrin, Radixin, Moesin)) that remodel and relocate cells. Also, PIP2 interacts with a vast number of intracellular receptors, kinases and enzymes to interrupt signaling pathways that regulate biological processes like cell division, proliferation and death. PIP2 is cleaved by enzymes such as phospholipases C (PLC) and phosphatases. PLC dries out PIP2 leaving two signaling molecules — diacylglycerol (DAG) and inositol triphosphate (IP3). As a lipid-second messenger, DAG engages PKC through several downstream signaling networks. IP3 then binds to IP3 receptors on the endoplasmic reticulum to push calcium ions into the cell. Such PIP2-like signaling molecules enable cells to directly act on factors, hormones and neurotransmitters external to them and regulate molecular-level cell growth, metabolism and differentiation. The PI3K can also phosphorylate PIP2 to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) for survival, proliferation and anti-apoptotic function.

Figure 1. Chemical Structures of Myo-Inositol, Phosphatidylinositol (PI), and Phosphatidylinositol(4,5)-Bisphosphate (PIP2). (Source: Harraz OF, et al., 2020)

In this cytoskeletal control, PIP2 also includes most of the mover-and-spin proteins and some of the intracellular proteins that control actin nucleation and depolymerization (Profilin, Cofilin). These signals regulate actin turnover and keep the cytoskeleton stable for cell migration, phagocytosis and exocytosis. PIP2, for example, drives cell migration by inducing Rho family GTPases to generate pseudopodia. PIP2 also binds calcium-binding proteins, including calmodulin, which changes calcium signaling and indirectly regulates actin dynamics. PIP2 homeostasis is essential both physiologically and pathologically. Recently, research has demonstrated that PIP2 is directly related to cancer development, neurodegeneration and inflammation. Low levels of PIP2 in tumor cells may influence PI3K/AKT signaling, further fueling cancer cell growth and survival. For instance, in many cancers, PI3K/AKT pathway abnormal activation promotes PIP2 metabolism, and inhibition of the pathway has anticancer effects. So too does PIP2, which is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's. The changes in PIP2 levels, it has been found, could break the membranes of neuron cells and result in apoptosis and cell death. In addition, the inflammatory-response regulation function of PIP2 has received considerable attention, in that it can regulate production and release of inflammatory factors, which influence immune systems and inflammatory diseases. PIP2 regulates calcium and sodium channels in the nervous system and this is vital to keeping the electrical activity of neurons running smoothly. PIP2 regulates neurotransmitter output, synaptic plasticity, and neuronal activity. It acts directly on calcium channels that control influx and expulsion of presynaptic calcium, making it more valuable for learning and memory. Additionally, PIP2 is involved in cardiomyocyte regulation by binding to calcium channels and controlling myocyte excitability and contractility. Therefore, research on PIP2 in the nervous and cardiovascular system offers enormous potential to identify new therapeutic approaches.

Figure 2. Cooperative and Independent Regulation of Melanoma or Other Cancer by PIP3 and MAPK Pathways. (Source: Mandal K, 2020)

The various techniques used to analyze PIP2's function and mechanisms are lipid chromatography, fluorescence microscopy, and X-ray crystallography. In recent years, CRISPR/Cas9 gene-editing technologies have brought new ways to explore PIP2-related genes. Through fluorescent tags, researchers were able to track PIP2 localization and movement better, within cell membranes, to see how PIP2 mapped to effector molecules over time. Single-molecule images and high-resolution microscopy have now permitted the monitoring in real time of PIP2's active adsorption of ion channels, G-protein-coupled receptors and signaling complexes to understand how PIP2 regulates signal transduction. Besides, drug discovery is investigating novel PIP2 modulators that could offer novel therapeutics for neurodegenerative, cardiovascular and inflammatory conditions. PIP2 is, in short, a signaling molecule and one that engages in all sorts of cellular processes and regulatory networks. It regulates cytoskeletal reorganization, ion channel regulation, cell motility, membrane protein activity, and has a wide-ranging regulatory function under physiological and pathological conditions. PIP2 research on cancer, neurodegenerative diseases and cardiovascular disease has revealed the role of PIP2 in the progression of disease, and several studies have attempted to mitigate these diseases by influencing PIP2 activity and levels. In the face of advancing research technologies, PIP2 presents an exciting opportunity to further unravel cell-to-cell signal transduction and craft novel therapeutics.

Figure 3. Effectors of PIP2 and PIP3. (Source: Tariq K, Luikart BW, 2021)

PIP2 Monoclonal Antibody
Anti-Phosphatidylinositol 4,5-bisphosphate
Monoclonal Anti-PIP2