The promoting role of lysosome-localized c-Src in autophagosome-lysosome fusion

Suzuki, Ko; Honda, Takeshi; Akatsu, Aki; Yamaguchi, Noritaka; Yamaguchi, Naoto

doi:10.1016/j.cellsig.2020.109774

Cited by 4 publications

(2 citation statements)

References 67 publications

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“…Based on extensively studies about the pathogenesis of those diseases, we think the potential pathophysiological mechanism related to SFKs has not been fully understood. At first, most of the above researches define SFKs as the plasma membrane, interestingly, SFKs are also found to localize to organelle membranes including Golgi membranes and lysosomal membranes and mitochondrial membranes [89]. The intracellular location is dynamic, such as the enrichment of activated Fyn in multivesicular bodies led to a defect in cell differentiation in a neuroblastoma cell line [90].…”

Section: Discussionmentioning

confidence: 99%

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

Zhai¹,

Yang²,

Zhang³

et al. 2021

Int. J. Med. Sci.

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The Src-family protein tyrosine kinases (SFKs), a subfamily of non-receptor tyrosine kinases, are ubiquitously expressed in various cell types. Numerous studies have suggested that SFKs are related to signal transduction in major cardiac physiological and pathological processes, it is the activity of SFKs that is connected with the maintenance of cardiovascular homeostasis. Upon stimulation of various injury factors or stress, the phosphorylation state of SFKs is changed, which has been found to modulate different cardiac pathological conditions, such as hypertension, coronary heart disease, ischemic heart disease, myocardial ischemia-reperfusion injury, arrhythmia and cardiomyopathy via regulating cell growth, differentiation, movement and function, electrophysiologic signals. This review summarizes the basic information about SFKs, updates its role in the different processes underlying the development of multiple cardiovascular diseases (CVDs), and highlights their potential role as disease biomarkers and therapeutic targets, which would help understand the pathophysiology of CVDs and promote the further potential clinical adhibition.

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Section: Discussionmentioning

confidence: 99%

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

Zhai¹,

Yang²,

Zhang³

et al. 2021

Int. J. Med. Sci.

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“…We hypothesized that TAT-Cx43 266-283 might block the autophagic flux through the inhibition of c-Src. Indeed, it was recently shown that lysosomal c-Src decreases LC3-II levels and autophagic flux in a kinase activity-dependent manner and that lysosomal c-Src and other Src family kinases promote autophagosome-lysosome fusion to maintain viability under nutrient starvation [ 64 ]. Surprisingly, dasatinib, a c-Src inhibitor, did not affect GSC survival under nutrient deprivation, indicating that the effect of dasatinib on other signaling pathways, including other members of the Src kinase family, BCR-ABL, c-KIT, PDGFR, and ephrin A2 [ 65 ], might be counteracting the effect on autophagy or that c-Src inhibition might not be sufficient to promote cell death in dormant GSCs.…”

Section: Discussionmentioning

confidence: 99%

Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43266-283 in Glioblastoma Stem Cells

Pelaz

Ollauri-Ibáñez

Lillo

et al. 2021

Cancers

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Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43266-283 effect. TAT-Cx43266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43266-283 as a therapy for this type of cancer.

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Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

Morii

Kubota

Hasegawa

et al. 2021

Sci Rep

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Src-family tyrosine kinases (SFKs) play important roles in a number of signal transduction events during mitosis, such as spindle formation. A relationship has been reported between SFKs and the mitotic spindle; however, the underlying mechanisms remain unclear. We herein demonstrated that SFKs accumulated in the centrosome region at the onset of mitosis. Centrosomal Fyn increased in the G2 phase in a microtubule polymerization-dependent manner. A mass spectrometry analysis using mitotic spindle preparations was performed to identify tyrosine-phosphorylated substrates. Protein regulator of cytokinesis 1 (PRC1) and kinastrin/small kinetochore-associated protein (kinastrin/SKAP) were identified as SFK substrates. SFKs mainly phosphorylated PRC1 at Tyr-464 and kinastrin at Tyr-87. Although wild-type PRC1 is associated with microtubules, phosphomimetic PRC1 impaired the ability to bind microtubules. Phosphomimetic kinastrin at Tyr-87 also impaired binding with microtubules. Collectively, these results suggest that tyrosine phosphorylation of PRC1 and kinastrin plays a role in their delocalization from microtubules during mitosis.

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The promoting role of lysosome-localized c-Src in autophagosome-lysosome fusion

Cited by 4 publications

References 67 publications

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43266-283 in Glioblastoma Stem Cells

Src-mediated tyrosine phosphorylation of PRC1 and kinastrin/SKAP on the mitotic spindle

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