Comprehensive knockout analysis of the Rab family GTPases in epithelial cells

Homma, Yuta; Kinoshita, Riko; Kuchitsu, Yoshihiko; Wawro, Paulina S.; Marubashi, Soujiro; Oguchi, Mai E.; Ishida, Morié; Fujita, Naonobu; Fukuda, Mitsunori

doi:10.1083/jcb.201810134

Cited by 74 publications

(94 citation statements)

References 62 publications

(88 reference statements)

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“…RAB6A has been implicated in matrix protein secretion, cell-matrix interactions and cell polarity in different models (Shafaq-Zadah et al, 2016;Fourrière et al, 2019;Homma et al, 2019). In contrast, our data indicate that loss of Rab6a in the luminal secretory lineage had no major impact on the structure of the mammary tissue.…”

Section: Loss Of Rab6a Affects Prlr Expression and Its Downstream Stacontrasting

confidence: 47%

“…Potentially, other RAB proteins, highly expressed in the luminal secretory cells, could participate in maintaining apico-basal polarity features, in particular RAB8, a RAB GTPase implicated in the same post-Golgi transport pathways than RAB6A (Goud and Akhmanova, 2012). In addition, although expressed at very low level in the mammary tissue, RAB6B could have some compensatory function in the absence of RAB6A, as reported for RAB6-KO MDCK cells (Homma et al, 2019).…”

Section: Although Less Enriched In Integrins Than Basal Cells Luminamentioning

confidence: 55%

“…Loss of RAB6A might thus perturb PRLR transport at different levels from Golgi to the plasma membrane, affecting its surface expression and thereby PRLinduced signaling events. Whether perturbation of intracellular PRLR transport leads to PRLR delivery to lysosomes for degradation, as reported for unsecreted cargos in RAB6-KO MDCK cells (Homma et al, 2019), remains to be determined.…”

Section: Loss Of Rab6a Affects Prlr Expression and Its Downstream Stamentioning

confidence: 97%

“…Loss of RAB6A during mouse embryogenesis and in migratory cell models has been reported to severely alter laminin and/or β1 integrin expression, perturbing cell adhesion and migration (Shafaq-Zadah et al, 2016). In MDCK cells, a model presenting an apico-basal polarity in 3D cultures, RAB6A/B knock-out (RAB6-KO) strongly inhibited the secretion of soluble cargos, including laminin, whereas it mildly impaired that of transmembrane proteins (Homma et al, 2019). Of note, despite their failure in laminin secretion, RAB6-KO MDCK cells were able to form polarized cysts in 3D cultures.…”

Section: Loss Of Rab6a Does Not Critically Affect the Polarized Organmentioning

confidence: 99%

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RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

Cayre

Faraldo

Bardin

et al. 2020

Preprint

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Running title: RAB6 in mammary secretory function Key words: RAB6 GTPase, mammary gland, luminal secretory cells, STAT5, PRL signaling SUMMARY STATEMENTThis study reveals a role for the Golgi-associated RAB GTPases, RAB6A/A', in the lactogenic function of the mammary gland. ABSTRACTThe Golgi-associated RAB GTPases, RAB6A and RAB6A', regulate anterograde and retrograde transport pathways from and to the Golgi. In vitro, RAB6A/A' have been reported to be involved in several cellular functions, including, in addition to transport, cell division, migration, adhesion and polarity. However, their role remains poorly described in vivo, in particular in epithelial tissues. Here, we generated BlgCre; Rab6a F/F mouse presenting a specific deletion of Rab6a in the mammary luminal secretory lineage during gestation and lactation. Rab6a loss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. It led to a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a human mammary epithelial cell line suggested that defective STAT5 activation might originate from a perturbed transport of the prolactin receptor, altering its membrane expression and signaling cascade. Despite the major functional defects observed upon Rab6a deletion, the polarized organization of the mammary epithelial bilayer was preserved.Altogether, our data reveal a crucial role for RAB6A/A' in the lactogenic function of the mammary gland. They also suggest that the trafficking pathways controlled by RAB6A/A' depend on cell type specialization and tissue context.

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Section: Loss Of Rab6a Affects Prlr Expression and Its Downstream Stacontrasting

confidence: 47%

Section: Although Less Enriched In Integrins Than Basal Cells Luminamentioning

confidence: 55%

Section: Loss Of Rab6a Affects Prlr Expression and Its Downstream Stamentioning

confidence: 97%

Section: Loss Of Rab6a Does Not Critically Affect the Polarized Organmentioning

confidence: 99%

See 2 more Smart Citations

RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

Cayre

Faraldo

Bardin

et al. 2020

Preprint

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“…Only for the Rab1A and Rab1B, it was shown that at least one of them is required for cell viability [39]. In contrast, double knockout of Rab11A and Rab11B or Rab6A and Rab6B showed that neither pair is required for cell viability [40].…”

Section: Golgi Rabsmentioning

confidence: 99%

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Lipatova

Segev

2019

FEBS Letters

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The conserved Ypt/Rab GTPases regulate the different steps of all intracellular trafficking pathways. Ypt/Rabs are activated by their specific nucleotide exchangers termed GEFs, and when GTP bound, they recruit their downstream effectors, which mediate vesicular transport substeps. In the yeast exocytic pathway, Ypt1 and Ypt31/32 regulate traffic through the Golgi and the conserved modular TRAPP complex acts a GEF for both Ypt1 and Ypt31/32. However, the precise localization and function of these Ypts have been under debate, as is the identity of their corresponding GEFs. We have established that Ypt1 and Ypt31 reside on the two sides of the Golgi, early and late, respectively, and regulate Golgi cisternal progression. We and others have shown that whereas a single TRAPP complex, TRAPP II, activates Ypt31, three TRAPP complexes can activate Ypt1: TRAPPs I, III, and IV. We propose that TRAPP I and II activate Ypt1 and Ypt31, respectively, at the Golgi, whereas TRAPP III and IV activate Ypt1 in autophagy. Resolving these issues is important because both Rabs and TRAPPs are implicated in multiple human diseases, ranging from cancer to neurodegenerative diseases.

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Newer Methods Drive Recent Insights into Rab GTPase Biology: An Overview

Segev

2021

Methods in Molecular Biology

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Comprehensive knockout analysis of the Rab family GTPases in epithelial cells

Cited by 74 publications

References 62 publications

RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Newer Methods Drive Recent Insights into Rab GTPase Biology: An Overview

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