Nucleotide exchange factor Rab3GEP requires DENN and non-DENN elements for activation and targeting of Rab27a

Sanza, Paolo; Evans, Richard D.; Briggs, Deborah A.; Cantero, Marta; Montoliu, Lluı́s; Patel, Shyamal; Sviderskaya, Elena V.; Itzen, Aymelt; Figueiredo, Ana C.; Seabra, Miguel C.; Hume, Alistair N.

doi:10.1242/jcs.212035

Cited by 10 publications

(16 citation statements)

References 49 publications

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“…For this reason, it is necessary to identify Rab-GEFs in order to understand the spatiotemporal regulation of Rabs. To date, at least Drr1 (Rab1-GEF), Rabex-5 (Rab5-GEF), Rabin8 (Rab8-GEF), Rab3GAP1/2 (Rab18-GEF), DENN/Rab3GEP (Rab27-GEF), and HPS1/4 (Rab32/38-GEF) have been shown to be necessary and/or sufficient for the proper localization of the corresponding Rabs [18][19][20][21]. In addition, some Rab-GEFs have been shown to also act as effectors of other Rabs (e.g., Rab8-GEFs Rabin8 and GRAB act as Rab11 effectors).…”

Section: Prenylation and Activationmentioning

confidence: 99%

Rab family of small GTPases: an updated view on their regulation and functions

2020

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The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane‐bound organelles and vesicles. Like other small GTPases, Rabs cycle between two states, an active (GTP‐loaded) state and an inactive (GDP‐loaded) state, and their cycling is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase‐activating proteins (GAPs). Because an active form of each Rab localizes on a specific organelle (or vesicle) and recruits various effector proteins to facilitate each step of membrane trafficking, knowing when and where Rabs are activated and what effectors Rabs recruit is crucial to understand their functions. Since the discovery of Rabs, they have been regarded as one of the central hubs for membrane trafficking, and numerous biochemical and genetic studies have revealed the mechanisms of Rab functions in recent years. The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post‐translational modifications, for example, phosphorylation, of Rabs. Rab functions beyond the simple effector‐recruiting model are also emerging. Furthermore, the recently developed CRISPR/Cas technology has enabled acceleration of knockout analyses in both animals and cultured cells and revealed previously unknown physiological roles of many Rabs. In this review article, we provide the most up‐to‐date and comprehensive lists of GEFs, GAPs, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions.

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Section: Prenylation and Activationmentioning

confidence: 99%

Rab family of small GTPases: an updated view on their regulation and functions

2020

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“…Thus, Rab3GEP functions as a dual GEF for Rab3 and Rab27 subfamily members in vivo. However, Rab27a can partially undergo activation and targeting in Rab3GEP-deficient melanocytes, which is suggested to occur based on the intrinsic high nucleotide exchange and low GTPase activities of Rab27a itself (Sanzà et al, 2019). Rab3GEP knockout in mice is lethal due to defective neuromuscular transmission (Tanaka et al, 2001), and these mice show a marked reduction in vesicular release probability without significant changes in the readily releasable pool size of their hippocampal neurons (Yamaguchi et al, 2002).…”

Section: Rab27 On Exocytic Vesicle Membranementioning

confidence: 99%

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Izumi

2021

Cell Struct. Funct.

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The monomeric GTPase Rab27 regulates exocytosis of a broad range of vesicles in multicellular organisms. Several effectors bind GTP-bound Rab27a and/or Rab27b on secretory vesicles to execute a series of exocytic steps, such as vesicle maturation, movement along microtubules, anchoring within the peripheral F-actin network, and tethering to the plasma membrane, via interactions with specific proteins and membrane lipids in a local milieu. Although Rab27 effectors generally promote exocytosis, they can also temporarily restrict it when they are involved in the rate-limiting step. Genetic alterations in Rab27-related molecules cause discrete diseases manifesting pigment dilution and immunodeficiency, and can also affect common diseases such as diabetes and cancer in complex ways. Although the function and mechanism of action of these 2 effectors have been explored, it is unclear how multiple effectors act in coordination within a cell to regulate the secretory process as a whole. It seems that Rab27 and various effectors constitutively reside on individual vesicles to perform consecutive exocytic steps. The present review describes the unique properties and in vivo roles of the Rab27 system, and the functional relationship among different effectors coexpressed in single cells, with pancreatic beta cells used as an example.

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“…Although Rab27A is present on mature melanosomes only when it is in its active, GTP‐bound state (Tarafder et al., 2011), a GTP‐locked constitutive active Rab27A(Q78L) mutant is mainly present in the cytosol and cannot support actin‐dependent melanosome transport (Ishida et al., 2014), suggesting that spatiotemporal regulation of Rab27A activity or GTP–GDP cycling of Rab27A is crucial. For activation of Rab27A, Rab3GEP (also known as DENN or MADD) contributes to Rab27A‐targeting to melanosomes; however, Rab3GEP is not the sole GEF of Rab27A in melanocytes, and the existence of an additional Rab27A‐GEF(s) has been suggested (Figueiredo et al., 2008; Sanzà et al., 2019; Tarafder et al., 2011). By contrast, EPI64 (also known as TBC1D10A) has the ability to inactivate Rab27A on melanosomes, and overexpression of EPI64 results in perinuclear melanosome aggregation (Itoh & Fukuda, 2006).…”

Section: Rab Gtpases In Melanosome Transport In Melanocytesmentioning

confidence: 99%

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

Fukuda

2020

Pigment Cell Melanoma Res

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Melanosomes are specialized intracellular organelles that produce and store melanin pigments in melanocytes, which are present in several mammalian tissues and organs, including the skin, hair, and eyes. Melanosomes form and mature stepwise (stages I–IV) in melanocytes and then are transported toward the plasma membrane along the cytoskeleton. They are subsequently transferred to neighboring keratinocytes by a largely unknown mechanism, and incorporated melanosomes are transported to the perinuclear region of the keratinocytes where they form melanin caps. Melanocytes also extend several dendrites that facilitate the efficient transfer of the melanosomes to the keratinocytes. Since the melanosome biogenesis, transport, and transfer steps require multiple membrane trafficking processes, Rab GTPases that are conserved key regulators of membrane traffic in all eukaryotes are crucial for skin and hair pigmentation. Dysfunctions of two Rab isoforms, Rab27A and Rab38, are known to cause a hypopigmentation phenotype in human type 2 Griscelli syndrome patients and in chocolate mice (related to Hermansky–Pudlak syndrome), respectively. In this review article, I review the literature on the functions of each Rab isoform and its upstream and downstream regulators in mammalian melanocytes and keratinocytes.

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Nucleotide exchange factor Rab3GEP requires DENN and non-DENN elements for activation and targeting of Rab27a

Cited by 10 publications

References 49 publications

Rab family of small GTPases: an updated view on their regulation and functions

Rab family of small GTPases: an updated view on their regulation and functions

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

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