The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors

Hanke-Gogokhia, Christin; Zhang, Houbin; Frederick, Jeanne M.; Baehr, Wolfgang

doi:10.1007/978-3-319-17121-0_87

Cited by 14 publications

(14 citation statements)

References 28 publications

(32 reference statements)

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“…Arl3 appears to be essential for cilia function as deletion leads to widespread ciliopathy and high levels of embryonic lethality ( 30 , 55 , 56 ). Arl3 function is regulated through its GAP RP2 and GEF Arl13b.…”

Section: Discussionmentioning

confidence: 99%

Arl3 and RP2 regulate the trafficking of ciliary tip kinesins

Schwarz¹,

Lane²,

Jovanović³

et al. 2017

Human Molecular Genetics

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Ciliary trafficking defects are the underlying cause of many ciliopathies, including Retinitis Pigmentosa (RP). Anterograde intraflagellar transport (IFT) is mediated by kinesin motor proteins; however, the function of the homodimeric Kif17 motor in cilia is poorly understood, whereas Kif7 is known to play an important role in stabilizing cilia tips. Here we identified the ciliary tip kinesins Kif7 and Kif17 as novel interaction partners of the small GTPase Arl3 and its regulatory GTPase activating protein (GAP) Retinitis Pigmentosa 2 (RP2). We show that Arl3 and RP2 mediate the localization of GFP-Kif17 to the cilia tip and competitive binding of RP2 and Arl3 with Kif17 complexes. RP2 and Arl3 also interact with another ciliary tip kinesin, Kif7, which is a conserved regulator of Hedgehog (Hh) signaling. siRNA-mediated loss of RP2 or Arl3 reduced the level of Kif7 at the cilia tip. This was further validated by reduced levels of Kif7 at cilia tips detected in fibroblasts and induced pluripotent stem cell (iPSC) 3D optic cups derived from a patient carrying an RP2 nonsense mutation c.519C > T (p.R120X), which lack detectable RP2 protein. Translational read-through inducing drugs (TRIDs), such as PTC124, were able to restore Kif7 levels at the ciliary tip of RP2 null cells. Collectively, our findings suggest that RP2 and Arl3 regulate the trafficking of specific kinesins to cilia tips and provide additional evidence that TRIDs could be clinically beneficial for patients with this retinal degeneration.

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Section: Discussionmentioning

confidence: 99%

Arl3 and RP2 regulate the trafficking of ciliary tip kinesins

Schwarz¹,

Lane²,

Jovanović³

et al. 2017

Human Molecular Genetics

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“…Moreover, a study has shown that regulation of Arf signaling reverses mutant protein toxicity in ALS by decreasing ER stress and stimulating various types of autophagy in cell lines and animal models (Zhai et al, 2015). Recent studies have shown that Arl proteins which belong to Arf GTPases are associated with retinitis pigmentosa (Veltel et al, 2008a; Zhang H. et al, 2015; Hanke-Gogokhia et al, 2016b). In the pathogenetic process of retinitis pigmentosa, Arl2/Arl3 signaling plays important roles in photoreceptor function by regulating lipid-modified membrane-associated proteins (Hanke-Gogokhia et al, 2016b).…”

Section: The Arf Subfamily In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

“…Recent studies have shown that Arl proteins which belong to Arf GTPases are associated with retinitis pigmentosa (Veltel et al, 2008a; Zhang H. et al, 2015; Hanke-Gogokhia et al, 2016b). In the pathogenetic process of retinitis pigmentosa, Arl2/Arl3 signaling plays important roles in photoreceptor function by regulating lipid-modified membrane-associated proteins (Hanke-Gogokhia et al, 2016b). The formation of a ternary complex between Arl3, its cognate GAP RP2 and its retinal effector HRG4 is also of great importance for photoreceptor function (Veltel et al, 2008b).…”

Section: The Arf Subfamily In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Qu¹,

Pan²,

et al. 2019

Front. Mol. Neurosci.

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The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), intellectual disability, epilepsy, drug addiction, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.

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“…Both RP2 and Arl3 localize to the connecting cilium of photoreceptors (Grayson et al, 2002). Arl3 has been linked to the trafficking of lipidated membrane-associated proteins (Hanke-Gogokhia et al, 2016a; Hanke-Gogokhia et al, 2016b). Defects Arl3-mediated trafficking of prenylated proteins in rod photoreceptors led to cell death and retinal degeneration (Wright et al, 2016) Although human mutations in ARL3 have not yet been identified, the Arl3 −/− knockout mice exhibit phenotypes consistent with ciliary defects (Schrick et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Developmental expression of the zebrafish Arf-like small GTPase paralogs arl13a and arl13b

Song

2018

Gene Expression Patterns

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Members of the Arf-like (Arl) family of small GTP-binding proteins regulate a number of cellular functions and play important roles in cilia structure and signaling. The small GTPase Arl13a is a close paralog to Arl13b, a small GTPase required for normal cilia formation that causes Joubert Syndrome when mutated. As mutation of arl13b causes a slow retinal degeneration in zebrafish (Song et al., 2016), we hypothesized that expression of arl13a may provide functional redundancy. We determined the expression domains of arl13a and arl13b during zebrafish development and examined subcellular localization by expression of fluorescence fusion proteins. Both genes are widely expressed during early cell division and gastrulation and Arl13a and Arl13b both localize to microtubules in ciliated and dividing cells of the early zebrafish embryo. Between 2 and 5 days post fertilization (dpf), arl13b is expressed in neural tissues while expression of arl13a is downregulated by 2 dpf and restricted to craniofacial structures. These results indicate that arl13a and arl13b have evolved different roles and that arl13a does not function in the zebrafish retina.

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The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors

Cited by 14 publications

References 28 publications

Arl3 and RP2 regulate the trafficking of ciliary tip kinesins

Arl3 and RP2 regulate the trafficking of ciliary tip kinesins

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Developmental expression of the zebrafish Arf-like small GTPase paralogs arl13a and arl13b

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