Interplay between phosphoinositide lipids and calcium signals at the leading edge of chemotaxing ameboid cells

•PI(3,4,5)P3 lipid has long been recognized as an important leading edge signal.•Recent progress has revealed the importance of PI(4,5)P2 lipid and its hydrolysis products diacylglycerol and Ins(1,4,5)P3.•Ca2+ has been a controversial leading edge signal but multiple lines of evidence from multiple laboratories now establish it as a central player with multiple regulatory roles.•Together, lipids and Ca2+ coordinate many key aspects of a complex but remarkably efficient network of leading edge signaling reactions.

The chemotactic migration of eukaryotic ameboid cells up concentration gradients is among the most advanced forms of cellular behavior. Chemotaxis is controlled by a complex network of signaling proteins bound to specific lipids on the cytoplasmic surface of the plasma membrane at the front of the cell, or the leading edge. The central lipid players in this leading edge signaling pathway include the phosphoinositides PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3), both of which play multiple roles. The products of PI(4,5)P2 hydrolysis, diacylglycerol (DAG) and Ins(1,4,5)P3 (IP3), are also implicated as important players. Together, these leading edge phosphoinositides and their degradation products, in concert with a local Ca2+ signal, control the recruitment and activities of many peripheral membrane proteins that are crucial to the leading edge signaling network. The present critical review summarizes the current molecular understanding of chemotactic signaling at the leading edge, including newly discovered roles of phosphoinositide lipids and Ca2+, while highlighting key questions for future research.