Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome

Goto‐Silva, Livia; McShane, Marisa P.; Salinas, Sara; Kalaidzidis, Yannis; Schiavo, Giampietro

doi:10.1038/s41598-019-38637-0

Cited by 28 publications

(20 citation statements)

References 65 publications

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“…By contrast, loss of Rab43 protein would impair Rab43 involved processes and impede the Akt activation. In support of our working model of Rab43 regulating Akt activation, Akt has been reported to facilitate Rab5 mediated endocytosis [33] and is able to promote the phosphorylation of Rab43 in pancreatic duct carcinoma cells [34]. Towards this end, more vigorous investigations are in need in the future.…”

Section: Discussionmentioning

confidence: 72%

A germline mutation in Rab43 gene identified from a cancer family predisposes to a hereditary liver-colon cancer syndrome

Jiang

Sun

et al. 2019

BMC Cancer

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Background Hereditary cancer syndromes have inherited germline mutations which predispose to benign and malignant tumors. Understanding of the molecular causes in hereditary cancer syndromes has advanced cancer treatment and prevention. However, the causal genes of many hereditary cancer syndromes remain unknown due to their rare frequency of mutation. Methods A large Chinese family with a history of hereditary liver-colon cancer syndrome was studied. The genomic DNA was extracted from the blood samples of involved family members, whole-exome sequencing was performed to identify genetic variants. Functional validation of a candidate variant was carried out using gene expression, gene knockout and immunohistochemistry. Results The whole-exome of the proband diagnosed with colon cancer was sequenced in comparison with his mother. A total of 13 SNVs and 16 InDels were identified. Among these variants, we focused on a mutation of Rab43 gene, a GTPase family member involving in protein trafficking, for further validation. Sanger DNA sequencing confirmed a mutation (c: 128810106C > T, p: A158T) occurred in one allele of Rab43 gene from the proband, that heterozygous mutation also was verified in the genome of the proband’s deceased father with liver cancer, but not in his healthy mother and sister. Ectopic expression of the Rab43 A158T mutant in Huh7 cells led to more enhanced cell growth, proliferation and migration compared to the expression of wild type Rab43. Conversely, knockout of Rab43 in HepG2 cells resulted in slow cell growth and multiple nuclei formation and impaired activation of Akt. Finally, a positive correlation between the expression levels of Rab43 protein and cancer development in that family was confirmed. Conclusions A germline mutation of Rab43 gene is identified to be associated with the onset of a familial liver-colon cancer syndrome. Our finding points to a potential role of protein trafficking in the tumorigenesis of the familial cancer syndrome, and helps the genetic counseling to the affected family members. Electronic supplementary material The online version of this article (10.1186/s12885-019-5845-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 72%

A germline mutation in Rab43 gene identified from a cancer family predisposes to a hereditary liver-colon cancer syndrome

Jiang

Sun

et al. 2019

BMC Cancer

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“…The neuron may be particularly sensitive to dysregulation of Rab5 activity for at least two main reasons: (1) Endocytosis and subsequent recycling (or not) regulate the concentration of neurotransmitter receptor density on the cell surface, determining signal strength [53,56,57]. For example, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis in hippocampal neurons leads to long-term depression (LTD), and Rab5 is essential in this process [56,58,59]; and (2) neurotrophin signaling from synapses is dependent on endocytosis, retrograde transport of endosomes along axons, and endosomal signaling [1,48,52,60].…”

Section: Rab5 Importance For Neuronal Functionmentioning

confidence: 99%

“…However, there are increasing examples, including in the context of cytokine signaling, that receptor endocytosis can increase signaling [140][141][142]. Further, in the context of the neuron endosomal signaling after axonal retrograde signaling, both the signaling pathways distinct from neurotrophins [60] and the cross-talk on the endosome between kinase pathways [143] are underexplored in terms of understanding their roles in modulating p38α (or p38 MAPK) signaling.…”

Section: Future Directions For Research and Prospectsmentioning

confidence: 99%

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Germann¹,

Alam²

2020

IJMS

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Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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“…Like other early endosome-associated proteins (e.g. Rab5) (Goto-Silva et al 2019), Hrs exhibits a mixture of anterograde, retrograde, and non-processive bidirectional motility ( Fig. 2F).…”

Section: Neuronal Activity Stimulates the Anterograde And Bidirectionmentioning

confidence: 96%

Axonal transport of Hrs is activity-dependent and rate limiting for synaptic vesicle protein degradation

Birdsall

Zhu

Kirwan

et al. 2020

Preprint

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Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy, functional synapses in neurons. Our previous work showed that the degradation of SV proteins is mediated by the endosomal sorting complex required for transport (ESCRT) pathway in an activity-dependent manner. Here, we characterize the axonal transport dynamics of ESCRT-0 proteins Hrs and STAM1, the first components of the ESCRT pathway critical for initiating SV protein degradation. Hrs-and STAM1-positive transport vesicles exhibit increased anterograde and bidirectional motility in response to neuronal firing, and frequent colocalization with SV pools. These ESCRT-0 vesicles are a subset of Rab5-positive structures in axons, likely representing pro-degradative early endosomes. Further, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of ESCRT-0 vesicles as well as the degradation of SV membrane proteins. Together, these data demonstrate a novel KIF13Adependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV proteins.Journal 32 (7): 954-69. https://doi.

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Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome

Cited by 28 publications

References 65 publications

A germline mutation in Rab43 gene identified from a cancer family predisposes to a hereditary liver-colon cancer syndrome

A germline mutation in Rab43 gene identified from a cancer family predisposes to a hereditary liver-colon cancer syndrome

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Axonal transport of Hrs is activity-dependent and rate limiting for synaptic vesicle protein degradation

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