Phosphoinositide signaling; from affinity probes to pharmaceutical targets.
Lipid signaling by phosphoinositides (PIP(n)s) involves an array of proteins with lipid recognition, kinase, phosphatase, and phospholipase functions. Understanding PIP(n) pathway signaling requires identification and characterization of PIP(n)-interacting proteins. Moreover, spatiotemporal localization and physiological function of PIP(n)-protein complexes must be elucidated in cellular and organismal contexts. For protein discovery to functional elucidation, reporter-linked phosphoinositides or tethered PIP(n)s have been essential. The phosphoinositide 3-kinase (PI 3-K) signaling pathway has recently emerged as an important source of potential "druggable" therapeutic targets in human pathophysiology in both academic and pharmaceutical environments. This review summarizes the chemistry of PIP(n) affinity probes and their use in identifying macromolecular targets. The process of target validation will be described, i.e., the use of tethered PIP(n)s in determining PIP(n) selectivity in vitro and in establishing the function of PIP(n)-protein complexes in living cells.
Prestwich
Glenn D
GD
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108, USA. glenn.prestwich@hsc.utah.edu
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D002846:Chromatography, Affinity; D015195:Drug Design; D006801:Humans; D051058:Oncogene Protein v-akt; D010449:Peptide Mapping; D010716:Phosphatidylinositols / Q000737:chemistry* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015682:Retroviridae Proteins, Oncogenic / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*
D002352:Carrier Proteins; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015682:Retroviridae Proteins, Oncogenic; D051058:Oncogene Protein v-akt