title: Robust spindle alignment in Drosophila neuroblasts by ultrasensitive activation of pins.
abstract: Cellular signaling pathways exhibit complex response profiles with features such as thresholds and steep activation (i.e., ultrasensitivity). In a reconstituted mitotic spindle orientation pathway, activation of Drosophila Pins (LGN in mammals) by Gαi is ultrasensitive (apparent Hill coefficient of 3.1), such that Pins recruitment of the microtubule binding protein Mud (NuMA) occurs over a very narrow Gαi concentration range. Ultrasensitivity is required for Pins function in neuroblasts as a nonultrasensitive Pins mutant fails to robustly couple spindle position to cell polarity. Pins contains three Gαi binding GoLoco domains (GLs); Gαi binding to GL3 activates Pins, whereas GLs 1 and 2 shape the response profile. Although cooperative binding is one mechanism for generating ultrasensitivity, we find GLs 1 and 2 act as "decoys" that compete against activation at GL3. Many signaling proteins contain multiple protein interaction domains, and the decoy mechanism may be a common method for generating ultrasensitivity in regulatory pathways.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Smith
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Prehoda
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D018797:Cell Cycle Proteins; D016764:Cell Polarity; D004330:Drosophila / Q000378:metabolism* / Q000648:ultrastructure; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D008565:Membrane Proteins; C411670:Mud protein, Drosophila; D009419:Nerve Tissue Proteins; C405164:Pins protein, Drosophila; D019206:GTP-Binding Protein alpha Subunits, Gi-Go