Notch Signaling: From the Outside In

Abstract

Development makes reiterative use of a surprisingly small set of essential molecular signals: the Wingless (Wg/ Wnt), Hedgehog (Hh), Transforming Growth Factor-b (TGFb), Receptor Tyrosine Kinase/Phosphotase (RTK/P) and Notch pathways (Gerhart, 1999). These five molecular archetypes act both individually and coordinately to interpret and transmit extrinsic signals as distinct cellular transcriptional responses. They mediate the establishment of polarity and body axes, coordinate pattern formation, and ultimately choreograph the morphogenesis of individual tissues. Recent advances have elucidated both the biochemical mechanisms regulating receptor activation and the molecular participants forming the intracellular signaling cascades of each of these pathways. A number of recent reviews have provided insight into the ever-expanding efforts directed at understanding Notch biology (Angerer and Angerer, 1999; Annaert and De Strooper, 1999; Artavanis-Tsakonas et al., 1999; Baker, 000; Beatus and Lendahl, 1998; Bertrand et al., 2000; Bray, 998a,b; Chan and Jan, 1998, 1999; Deftos and Bevan, 2000; reenwald, 1998; Gridley, 1997; Hoyne et al., 2000; Joutel nd Tournier-Lasserve, 1998; Kimble et al., 1998; Lewis, 998; Miele and Osborne, 1999; Panin and Irvine, 1998; erron and Harris, 2000; Robey, 1999; Rooke and Xu, 1998; aito and Watanabe, 1998; Selkoe, 2000; Weinmaster, 1997, 000). In this review we summarize the efforts of many roups that, over the past decade, contributed to the discovry that a novel signaling paradigm, Regulated Intramembrane Proteolysis (RIP), controls Notch receptor activation. In addition to Notch, the RIP paradigm has recently been shown to impact a number of other proteins (Brown et al., 2000). RIP utilizes “dual address” proteins which function at two discrete subcellular locations. The full-length “receptor” is first held at a docking site where, in response to stimulus/ligand, it undergoes intramembranous proteolysis to release a subdomain that then translocates to a second site of action, typically the nucleus. In the case of Notch,