The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block

Ghosh, Pradipta; Rangamani, Padmini; Kufareva, Irina

doi:10.1080/15384101.2017.1282584

Cited by 40 publications

(57 citation statements)

References 40 publications

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“…Among these accessory proteins, the recently delineated family of guanine-nucleotide exchange modulators, or GEMs (4,5), stands out due to their ability to modulate heterotrimeric G proteins independently of GPCRs. GEMs are cytosolic proteins that uniquely act as GEFs for Gαi and as GDIs for Gαs, all using the same evolutionarily conserved GEM motif (6,7).…”

Section: Structural Basis For Gpcr-independent Activation Of Heterotrmentioning

confidence: 99%

“…GEMs are cytosolic proteins that uniquely act as GEFs for Gαi and as GDIs for Gαs, all using the same evolutionarily conserved GEM motif (6,7). The motif was initially identified based on homology to the synthetic peptide KB752 that can bind and activate Gαi (8); however, the motif has since been found in several naturally occurring proteins (5). The ability of GEMs to activate Gαi in live cells downstream of diverse classes of receptors has been demonstrated by various approaches: Dissociation of Gβγ subunits from Gαi was shown using fluorescence and bioluminescence resonance energy transfer (FRET/ BRET)-based reporters (9)(10)(11), Gαi activation by conformationspecific antibodies (12), and reduction in cellular cAMP by radioimmunoassay (12).…”

Section: Structural Basis For Gpcr-independent Activation Of Heterotrmentioning

confidence: 99%

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Structural basis for GPCR-independent activation of heterotrimeric Gi proteins

Kalogriopoulos

Rees

Ngo

et al. 2019

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

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Heterotrimeric G proteins are key molecular switches that control cell behavior. The canonical activation of G proteins by agonist-occupied G protein-coupled receptors (GPCRs) has recently been elucidated from the structural perspective. In contrast, the structural basis for GPCR-independent G protein activation by a novel family of guanine-nucleotide exchange modulators (GEMs) remains unknown. Here, we present a 2.0-Å crystal structure of Gαi in complex with the GEM motif of GIV/Girdin. Nucleotide exchange assays, molecular dynamics simulations, and hydrogen–deuterium exchange experiments demonstrate that GEM binding to the conformational switch II causes structural changes that allosterically propagate to the hydrophobic core of the Gαi GTPase domain. Rearrangement of the hydrophobic core appears to be a common mechanism by which GPCRs and GEMs activate G proteins, although with different efficiency. Atomic-level insights presented here will aid structure-based efforts to selectively target the noncanonical G protein activation.

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Section: Structural Basis For Gpcr-independent Activation Of Heterotrmentioning

confidence: 99%

Section: Structural Basis For Gpcr-independent Activation Of Heterotrmentioning

confidence: 99%

Structural basis for GPCR-independent activation of heterotrimeric Gi proteins

Kalogriopoulos

Rees

Ngo

et al. 2019

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

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“…Small GTP-converting enzymes, GTPases, ranging in size from 20 to 40 KDa, are essential for the efficient completion of many physiologic and developmental processes ( Peck et al, 2002 ; Moon and Zheng, 2003 ; Jiang and Ramachandran, 2006 ; Tcherkezian and Lamarche-Vane, 2007 ; De Filippis et al, 2014 ; Ghosh et al, 2017 ). The GTPases switch between an active GTP-bound state and an inactive GDP-bound form as illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory

Nowak

2018

eNeuro

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Small GTP-converting enzymes, GTPases, are essential for the efficient completion of many physiological and developmental processes. They are regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Arhgap39, also known as preoptic regulatory factor-2 (Porf-2) or Vilse, a member of the Rho GAP group, was first identified in 1990 in the rat CNS. It has since been shown to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. It plays a pivotal role in neurodevelopment and learning and memory. Homologous or orthologous genes are found in more than 280 vertebrate and invertebrate species, suggesting preservation through evolution. Not surprisingly, loss of the Arhgap39/Porf-2 gene in mice manifests as an embryonic lethal condition. Although Arhgap39/Porf-2 is highly expressed in the brain, it is also widely distributed throughout the body, with potential additional roles in oncogenesis and morphogenesis. This review summarizes, for the first time, the known information about this gene under its various names, in addition to considering its transcripts and proteins. The majority of findings described have been made in rats, mice, humans, and fruit flies. This work surveys the known functions, functional mediators, variables modifying expression and upstream regulators of expression, and potential physiological and pathological roles of Arhgap39/Porf-2 in health and disease.

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“…The fact that both overactivation of aPKC or inhibition of its activity is deleterious to epithelial cell polarity and cyst morphogenesis may underlie the conflicting interpretations of the data in the literature [34,55]. GIRDIN is also known to modulate heterotrimeric G protein signaling [56,57]-a role that seems to contribute to the formation of normal cysts by MDCK cells [38]. In addition, it was demonstrated recently that GIRDIN acts as an effector of AMP-activated protein kinase (AMPK) under energetic stress to maintain tight junction function [39].…”

Section: Discussionmentioning

confidence: 99%

Girdin is a component of the lateral polarity protein network restricting cell dissemination

et al. 2020

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Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIR-DIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.

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The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block

Cited by 40 publications

References 40 publications

Structural basis for GPCR-independent activation of heterotrimeric Gi proteins

Structural basis for GPCR-independent activation of heterotrimeric Gi proteins

Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory

Girdin is a component of the lateral polarity protein network restricting cell dissemination

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