PIP2 and PIP3: Complex Roles at the Cell Surface

• Published in: Cell 2000-03, Vol.100 (6), p.603-606
• Main Author: Czech, Michael P
• Format: Article
• Language: English
• Subjects: Cell Cycle Proteins - physiology; diacylglycerol; Fungal Proteins - physiology; gelsolin; Membrane Proteins - physiology; phosphatidylinositol 3,4,5-trisphosphate; phosphatidylinositol 4,5-bisphosphate; profilin; Saccharomyces cerevisiae Proteins; synaptojanin 1; Transcription Factors - physiology; Yeasts - cytology; Yeasts - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80696-0

Phosphatidylinositol (4,5)-bisphosphate (PIP2) and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) represent less than 1% of membrane phospholipids, yet they function in a remarkable number of crucial cellular processes. These low-abundance polyphosphoinositides direct two major independent signaling cascades. PIP3 is the effector of multiple downstream targets of the phosphoinositide 3 kinase (PI3K) pathway (Rameh and Cantley, 1999); PIP2 is the precursor of the mediators diacylglycerol and inositol(1,4,5)P3 following its hydrolysis by hormone-sensitive phospholipase C (PLC) enzymes. New experiments are now revealing yet another signaling mode controlled by PIP2 (Toker, 1998; Honda et al., 1999; Raucher et al., 2000). This novel cascade depends on intact PIP2 rather than products of its hydrolysis. Recent work demonstrates not only new signaling functions of PIP2 but also intricate regulation of membrane phospholipids. New insights on these events highlight the cell surface membrane as a major site of action of both PIP2 and PIP3 and reveal unexpected crosstalk between these polyphosphoinositides. PIP3 and other PI3K products control many processes at the plasma membrane, including phagocytosis, pinocytosis, regulated exocytosis, and cytoskeletal organization. Recent studies also implicate PIP2 in an impressive number of key cell surface events (Table 1). These include fundamental processes in membrane trafficking and plasma membrane-cytoskeleton linkages. Gelsolin, profilin, and other key regulators of the actin cytoskeleton associate with PIP2 through defined basic residues within their sequences (Toker, 1998). Recent results also reveal a role for PIP2 in binding and activating proteins that connect the plasma membrane to the actin cytoskeleton. A role for PIP2 in membrane ruffling requiring actin reorganization is also apparent (Honda et al., 1999). Several proteins that regulate the formation and function of clathrin-coated vesicles in endocytosis, including the AP-2 adaptor, AP180, dynamin, and synaptotagmin, also bind PIP2. Synaptojanin-1, a PIP2 phosphatase, is a constituent of clathrin-coated membranes and is required for normal endocytosis and recycling of synaptic vesicles (Cremona et al., 1999). Regulated exocytosis is also PIP2 dependent, evidenced by the requirements for enzymes that direct its synthesis in the priming/fusion step at the plasma membrane (Loyet et al., 1998).