Multiple Role of Inositides in Signal Transduction

In recent years, PI(4,5)P2 has been shown to be not only the source of second messengers at the plasma membrane, but also to be directly involved in regulating a daunting number of cellular processes, including assembly and regulation of the actin cytoskeleton, and of the intracellular trafficking of exo and endocytotic vesicles (Czech, 2002). PI(4,5)P2 is localized in distinct subdomains of the plasma membrane, as well as at the Golgi stacks and endoplasmic reticulum. Its bisphos-phorylated isomers PI(3,4)P2 and PI(3,5)P2 are involved in the trafficking of multivesicular bodies, or in anion superoxide production after phagocytosis, respectively (Cooke, 2002; Cullen et al., 2001). Also PI(3,4,5)P3 regulates vesicular trafficking, actin dynamics, and cell proliferation (Toker, 2002), whilst PI(3)P modulates endosomal trafficking, ion channel regulation, and cell survival (Osborne et al., 2001). The soluble head-group IP3 is also the precursor to a family of inositol polyphosphates involved in the intracellular calcium homeostasis, ion channel physiology, and membrane dynamics (Irvine and Schell, 2001).

The multiplicity of phosphoinositide functions also depends on their ability to be segregated at different intracellular compartments, characterized by a specific set of interacting proteins (Fig. 1). In fact, phosphoinositides can act directly as

Fig. 1 Multiple roles of inositides in signal transduction. PI(4,5)P2 is indicated both as precursor of second messengers (black arrows) and as a direct signalling molecule (open arrows). Through interaction with protein modules (grey italics) it affects vesicle trafficking and actin cytoskeleton assembly. In the upper part of the drawing is represented the recruitment, at the membrane-associated receptor, of the elements of the signalling cascade. PKC isoforms are the target of DAG and Ca2+ and provide phosphorylation of cytoplasmic transcription factors. PKC isoforms and Ca2+ can also be translocated to the nucleus (bent arrows). Graphic outlines used in this and other drawings: black square, inositol PLC isoforms; open square, lipid kinases; gray square, inositol-derived second messengers; grey italics, molecular targets

Fig. 1 Multiple roles of inositides in signal transduction. PI(4,5)P2 is indicated both as precursor of second messengers (black arrows) and as a direct signalling molecule (open arrows). Through interaction with protein modules (grey italics) it affects vesicle trafficking and actin cytoskeleton assembly. In the upper part of the drawing is represented the recruitment, at the membrane-associated receptor, of the elements of the signalling cascade. PKC isoforms are the target of DAG and Ca2+ and provide phosphorylation of cytoplasmic transcription factors. PKC isoforms and Ca2+ can also be translocated to the nucleus (bent arrows). Graphic outlines used in this and other drawings: black square, inositol PLC isoforms; open square, lipid kinases; gray square, inositol-derived second messengers; grey italics, molecular targets signals, because their polar heads recognize protein domains, such as plekstrin homology (PH) or src oncogene homology (SH) domain. Since the affinity of phos-phoinositides to proteins can greatly vary, the localization of a phosphoinositide at a given site induces a lipid-dependent segregation of the related enzymes, including lipid kinases and lipases (Anderson et al., 1999). Many of the actin-regulating proteins, such as profilin, gelsolin, and vinculin, present protein affinity domains to PI(4,5)P2. The presence of this lipid substrate at the cytoskeleton level is able to segregate at the same site some lipid kinases and phospholipases. In this sense, actin microfilaments behave as a platform to coordinate the different constituents of the signalling system. For example, it is known that PLCy recognizes a SH3 domain of profilin; because PI(4,5)P2 associated to profilin is the elective substrate of PLCy, this results in the formation of actin-profilin complexes, that prevent actin polymerization. An inverse effect is caused by PI(3,4,5)P3 (Toker, 2002).

The complexity of the system is further increased by the observed translocation of some phosphoinositide-related enzymes in response to agonists. Generally, indeed, cytosolic enzymes are translocated to membrane receptors upon agonist stimulation. However, since lipid substrates capable of sequestering enzymes are located at other cellular sites, translocations involve also other districts. For example, PI-3 kinase, depending on the agonist, translocates to the plasma membrane, the microtubule organizing centre, intracellular vesicles, cytoskeleton, or to the nucleus.

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