Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes

Hume, Alistair N.; Ushakov, Dmitry S.; Tarafder, Abul K.; Ferenczi, Michael A.; Seabra, Miguel C.

doi:10.1242/jcs.010207

Cited by 93 publications

(103 citation statements)

References 40 publications

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“…4, B-H). In Rab27a-deficient ashen melanocytes, a dramatic decrease in Mlph levels is observed in comparison with wild-type cells, suggesting that Mlph requires interaction with Rab27a-GTP for stability (23). Therefore, we hypothesized that loss of Rab27-GTP in Rab3GEP-depleted cells would result in Mlph destabilization.…”

Section: Down-regulation Of Rab3gep In Melanocytes Results Inmentioning

confidence: 98%

Rab3GEP Is the Non-redundant Guanine Nucleotide Exchange Factor for Rab27a in Melanocytes

Figueiredo

Wasmeier

Tarafder

et al. 2008

Journal of Biological Chemistry

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Rab GTPases regulate discrete steps in vesicular transport pathways. Rabs require activation by specific guanine nucleotide exchange factors (GEFs) that stimulate the exchange of GDP for GTP. Rab27a controls motility and regulated exocytosis of secretory granules and related organelles. In melanocytes, Rab27a regulates peripheral transport of mature melanosomes by recruiting melanophilin and myosin Va. Here, we studied the activation of Rab27a in melanocytes. We identify Rab3GEP, previously isolated as a GEF for Rab3a, as the non-redundant Rab27a GEF. Similar to Rab27a-deficient ashen melanocytes, Rab3GEP-depleted cells show both clustering of melanosomes in the perinuclear area and loss of the Rab27a effector Mlph. Consistent with a role as an activator, levels of Rab27a-GTP are decreased in cells lacking Rab3GEP. Recombinant Rab3GEP exhibits guanine nucleotide exchange activity against Rab27a and Rab27b in vitro, in addition to its previously documented activity against Rab3. Our results indicate promiscuity in Rab GEF action and suggest that members of related but functionally distinct Rab subfamilies can be controlled by common activators.

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Section: Down-regulation Of Rab3gep In Melanocytes Results Inmentioning

confidence: 98%

Rab3GEP Is the Non-redundant Guanine Nucleotide Exchange Factor for Rab27a in Melanocytes

Figueiredo

Wasmeier

Tarafder

et al. 2008

Journal of Biological Chemistry

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“…However, MITF silencing obviously affects the distribution of both Tyrp1 and Silver containing vesicles. Rab27A has been reported to stabilize MLPH (20). Thus the loss of rab27 in MITF-silenced cells was expected to decrease MLPH expression.…”

Section: Discussionmentioning

confidence: 99%

Microphthalmia-associated Transcription Factor Regulates RAB27A Gene Expression and Controls Melanosome Transport

Chiavérini

Beuret

Flori

et al. 2008

Journal of Biological Chemistry

100

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Melanosomes are lysosome-related organelles specialized in melanin synthesis and transport. In this study, we show that microphthalmia-associated transcription factor (MITF) silencing induces melanosome gathering around the nucleus and causes the relocalization of Rab27A, Slac2a-Mlph, and Myo5a that control the transport of melanosomes on the actin network. In an attempt to elucidate the mechanism by which MITF controls melanosome distribution, we identify RAB27A as a new MITF target gene. Indeed, MITF silencing leads to a dramatic decrease in Rab27A expression and blocks the stimulation of Rab27A expression evoked by cAMP. Further, forced expression of MITF increases Rab27A expression, indicating that MITF is required and sufficient for Rab27A expression in melanoma cells. MITF binds to two E-boxes in the proximal region of the Rab27A promoter and stimulates its transcriptional activity. Finally, re-expression of Rab27A, in MITF-depleted cells, restores the transport of melanosomes to the cell periphery. These results show that RAB27A is a new direct transcriptional target of MITF and link MITF to melanosome transport, another key parameter of melanocyte differentiation and skin pigmentation. Interestingly, Rab27A is involved in other fundamental physiological functions, such as the transport of lytic granules and insulin secretion. Thus our results, deciphering the mechanism of Rab27A transcriptional regulation, have an interest that goes beyond the skin pigmentation field.

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“…Furthermore, Rab27a is required for exocytosis of secretory endo-lysosomes in non-specialised fibroblast-like cells (Laulagnier et al, 2011). Besides, Rab27a is responsible for the peripheral localisation of melanosomes (Hume et al, 2007) as well as of WPBs (Nightingale et al, 2009 and supplementary material Fig. S9).…”

Section: Discussionmentioning

confidence: 99%

Rab-genome analysis reveals novel insights in Weibel-Palade body exocytosis

Zografou

Basagiannis

Papafotika

et al. 2012

Journal of Cell Science

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SummaryWeibel-Palade bodies (WPBs) are endothelial-cell-specific organelles that, upon fusion with the plasma membrane, release cargo molecules that are essential in blood vessel abnormalities, such as thrombosis and inflammation, as well as in angiogenesis. Despite the importance of WPBs, the basic mechanisms that mediate their secretion are only poorly understood. Rab GTPases play fundamental role in the trafficking of intracellular organelles. Yet, the only known WPB-associated Rabs are Rab27a and Rab3d. To determine the full spectrum of WPB-associated Rabs we performed a complete Rab screening by analysing the localisation of all Rabs in WPBs and their involvement in the secretory process in endothelial cells. Apart from Rab3 and Rab27, we identified three additional Rabs, Rab15 (a previously reported endocytic Rab), Rab33 and Rab37, on the WPB limiting membrane. A knockdown approach using siRNAs showed that among these five WPB Rabs only Rab3, Rab27 and Rab15 are required for exocytosis. Intriguingly, we found that Rab15 cooperates with Rab27a in WPB secretion. Furthermore, a specific effector of Rab27, Munc13-4, appears to be also an effector of Rab15 and is required for WPB exocytosis. These data indicate that WPB secretion requires the coordinated function of a specific group of Rabs and that, among them, Rab27a and Rab15, as well as their effector Munc13-4, cooperate to drive exocytosis.

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Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes

Cited by 93 publications

References 40 publications

Rab3GEP Is the Non-redundant Guanine Nucleotide Exchange Factor for Rab27a in Melanocytes

Rab3GEP Is the Non-redundant Guanine Nucleotide Exchange Factor for Rab27a in Melanocytes

Microphthalmia-associated Transcription Factor Regulates RAB27A Gene Expression and Controls Melanosome Transport

Rab-genome analysis reveals novel insights in Weibel-Palade body exocytosis

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