Return of the GDI: The GoLoco Motif in Cell Division

Willard, Francis S.; Kimple, Randall J.; Siderovski, David P.

doi:10.1146/annurev.biochem.73.011303.073756

Cited by 188 publications

(207 citation statements)

References 102 publications

(151 reference statements)

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“…Domain dissection analysis showed that the C-terminus of LGN was responsible for its cortical localization and polarization, consistent with the findings that LGN C-terminus could localize to the cortex in mammalian cell lines [15][16][17]. The LGN C-terminus consists of four GoLoco motifs, which are capable of binding to heterotrimeric G protein α-subunits and functioning as guanine nucleotide dissociation inhibitors [22]. In mammalian cell lines, Gα subunits of heterotrimeric G proteins have been shown to be required for LGN cortical localization [15].…”

Section: Discussionsupporting

confidence: 82%

“…Like other Pins homologs, LGN contains seven tetratricopeptide repeat (TPR) motifs in its amino-terminal region and four Gαi/o-Loco (GoLoco) motifs in its carboxyl-terminal region [22]. To understand the functions of these two distinct regions, we dissected LGN LGN-N-GFP was distributed in the cytoplasm in both GV and MI oocytes.…”

Section: Localization and Function Of Lgn N-terminal And Cterminal Rementioning

confidence: 99%

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Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Guo

Gao

2009

Cell Res

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Mouse oocytes undergo polarization during meiotic maturation, and this polarization is essential for asymmetric cell divisions that maximize retention of maternal components required for early development. Without conventional centrosomes, the meiotic spindle has less focused poles and is barrel-shaped. The migration of meiotic spindles to the cortex is accompanied by a local reorganization and polarization of the cortex. LGN is a conserved protein involved in cell polarity and regulation of spindle organization. In the present study, we characterized the localization dynamics of LGN during mouse oocyte maturation and analyzed the effects of LGN upregulation and downregulation on meiotic spindle organization. At the germinal vesicle stage, LGN is distributed both cytoplasmically and at the cortex. During maturation, LGN localizes to the meiotic spindle apparatus and cortical LGN becomes less concentrated at the actin cap region. Excessive LGN induces meiotic spindle organization defects by elongating the spindle and enhancing pole focusing, whereas depletion of LGN by RNA interference results in meiotic spindle deformation and chromosome misalignment. Furthermore, the N-terminus of LGN has the ability of full-length LGN to regulate spindle organization, whereas the C-terminus of LGN controls cortical localization and polarization. Our results reveal that LGN is cortically polarized in mouse oocytes and is critical for meiotic spindle organization.

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Section: Discussionsupporting

confidence: 82%

Section: Localization and Function Of Lgn N-terminal And Cterminal Rementioning

confidence: 99%

Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Guo

Gao

2009

Cell Res

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“…1D), the distinct G␣i binding behavior in full-length Pins suggests that Pins contains one GoLoco domain that is unregulated or only partially regulated by the intramolecular interaction and two GoLoco domains that are cooperatively repressed. To further explore this model, we inactivated one or more GoLocos by mutating a single critical arginine residue (20) to phenylalanine in the context of fulllength Pins. These mutations do not inhibit the ability of the TPRs and GoLocos to interact (SI Fig.…”

Section: Differential Goloco Regulation By the Pins Intramolecular Inmentioning

confidence: 99%

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Nipper

Siller

Smith

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

108

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Drosophila neuroblasts divide asymmetrically by aligning their mitotic spindle with cortical cell polarity to generate distinct sibling cell types. Neuroblasts asymmetrically localize G␣i, Pins, and Mud proteins; Pins/G␣i direct cortical polarity, whereas Mud is required for spindle orientation. It is currently unknown how G␣i-Pins-Mud binding is regulated to link cortical polarity with spindle orientation. Here, we show that Pins forms a ''closed'' state via intramolecular GoLoco-tetratricopeptide repeat (TPR) interactions, which regulate Mud binding. Biochemical, genetic, and live imaging experiments show that G␣i binds to the first of three Pins GoLoco motifs to recruit Pins to the apical cortex without ''opening'' Pins or recruiting Mud. However, G␣i and Mud bind cooperatively to the Pins GoLocos 2/3 and tetratricopeptide repeat domains, respectively, thereby restricting Pins-Mud interaction to the apical cortex and fixing spindle orientation. We conclude that Pins has multiple activity states that generate cortical polarity and link it with mitotic spindle orientation.cell polarity ͉ cell signaling ͉ differentiation ͉ protein-protein interactions I n complex, multicellular organisms, differentiated cell types are needed to perform diverse functions. One common mechanism for cellular differentiation is asymmetric cell division, in which the mitotic spindle is aligned with the cell polarity axis to generate molecularly distinct sibling cells (1-4). Asymmetric divisions have been proposed to regulate stem cell pool size during development, adult tissue homeostasis, and the uncontrolled proliferation observed in cancer (5). Thus, understanding how the mitotic spindle is coupled to the cell polarity axis is relevant to stem cell and cancer biology. Here, we investigate this question in Drosophila neuroblasts, a model system for studying asymmetric cell division.Drosophila neuroblasts are stem cell-like progenitors that divide asymmetrically to produce a larger self-renewing neuroblast and a smaller ganglion mother cell (GMC) that differentiates into neurons or glia (3). Mitotic neuroblasts segregate factors that promote neuroblast self-renewal to their apical cortex and differentiation factors to their basal cortex. Precise alignment of the mitotic spindle with the neuroblast apical/basal polarity is required for asymmetric cell division and proper brain development: spindle misalignment leads to symmetric cell divisions that expand the neuroblast population and brain size (6-8).

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“…Sequence analysis indicates that AGS3 consists of a three-module structure. The N-terminal part of AGS3 contains seven tetratricopeptide repeats [the TPR domain (2)], a mediator of protein-protein interaction, whereas the C-terminal part contains four G protein regulatory motifs [the GPR or GoLoco domain (3)], a modulator of G protein signaling. The GPR domain of AGS3 preferentially binds and stabilizes GDP-bound G␣i subunits (4)(5)(6).…”

mentioning

confidence: 99%

A specific role of AGS3 in the surface expression of plasma membrane proteins

Groves

Gong

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Activator of G protein signaling 3 (AGS3), originally identified in a functional screen for mammalian proteins that activate heterotrimeric G protein signaling, is known to be involved in drug-seeking behavior and is up-regulated during cocaine withdrawal in animal models. These observations indicate a potential role for AGS3 in the formation or maintenance of neural plasticity. We have found that the overexpression of AGS3 alters the surface-to-total ratios of a subset of heterologously expressed plasma membrane receptors and channels. Further analysis of the endocytic trafficking of one such protein by a biotin-based internalization assay suggests that overexpression of AGS3 moderately affects the internalization or recycling of surface proteins. Moreover, AGS3 overexpression and siRNA-mediated knockdown of AGS3 both result in the dispersal of two endogenously expressed trans-Golgi network (TGN)-associated cargo proteins without influencing those in the cis-or medial-Golgi compartments. Finally, adding a TGN-localization signal to a CD4-derived reporter renders the trafficking of fusion protein sensitive to AGS3. Taken together, our data support a model wherein AGS3 modulates the protein trafficking along the TGN/plasma membrane/endosome loop. drug addiction ͉ Golgi apparatus ͉ membrane trafficking ͉ receptors and channels

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Return of the GDI: The GoLoco Motif in Cell Division

Cited by 188 publications

References 102 publications

Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Pins homolog LGN regulates meiotic spindle organization in mouse oocytes

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

A specific role of AGS3 in the surface expression of plasma membrane proteins

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