Phosphoinositide-metabolizing enzymes at the interface between membrane traffic and cell signalling

Abstract

Phosphoinositides (PIs) have long been known to have important roles in cell signalling. During the past decade, it has become clear that these lipids also act as constitutive signals that aid in defining organelle identity, and are short-lived recruiters and regulators of cytoskeletal and membrane dynamics. Recent studies have provided important clues as to how regulated activation of PI-metabolizing enzymes and recruitment of their binding proteins might cooperate in targeting distinct pools of PIs to different cell physiological functions.

Figure 1

Phosphoinositides and their metabolizing enzymes in exo-endocytic membrane traffic. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) and the corresponding metabolizing enzymes are required for fusion of secretory vesicles (SVs), formation of endocytic clathrin-coated pits (CCPs) and changes in actin dynamics. Phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂) delineate sorting stations for endocytic cargo through multivesicular bodies (MVBs) en route to the lysosome. Phosphatidylinositol 4-phosphate (PI(4)P) confers identity to the Golgi complex, and is required for trafficking of secretory cargo and perhaps lysosomal enzymes (not shown). PIs, phosphoinositides; PI(3)K, phosphatidylinositol 3-kinase; PI(4)K, phosphatidylinositol 4-kinase; PI(5)K, phosphatidylinositol 5-kinase; PIP(5)K, phosphatidylinositol phosphate 5-kinase.

Figure 2

Possible mechanisms for synthesizing and maintaining spatially restricted phosphoinositide pools. Spatiotemporal regulation of PI pools, for example, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) as schematically depicted here, might be achieved by a combination of several mechanisms, including locally restricted PI synthesis by regulated consecutive activation of PI kinases (a, d), recruitment of PI-specific effector proteins (b) or protein-mediated sequestration (c), and protection of the PI headgroup from enzymatic hydrolysis and degradation (e). PI, phosphoinositide.

Figure 3

Domain structure of major phosphoinositide-metabolizing enzymes. PI phosphatases, such as synaptojanin 1 and oculocerebrorenal syndrome of Lowe (OCRL), harbour clathrin and adaptor protein complex 2 (AP-2) adaptor-binding peptide motifs that target the enzymatic activity to clathrin-coated pits. Rho-GTPase activating protein (RhoGAP) or proline-rich domains (PRDs) might aid in targeting OCRL or synaptojanin 1 to specific intracellular or actin-rich membrane sites. Targeting domains or peptide motifs within PI kinases remain less well defined, although some enzymes, such as PIP(5)K Iγ-p90 or PI(4)K IIβ, contain cargo-like sorting motifs that might associate with AP adaptor complexes. PIK-fyve harbours a phosphatidylinositol 3-phosphate (PI(3)P)-specific binding FYVE domain aiding localization to the endosomal-lysosomal system. DEP, domain present in Disheveled, EGL-10 and Pleckstrin; PI, phosphoinositide; PI(4)K, phosphatidylinositol 4-kinase; PIP(5)K, phosphatidylinositol phosphate 5-kinase; Sac1, yeast suppressor of actin 1; TCP-1, tailless complex polypeptide-1.

Michael Krauß & Volker Haucke