A Phosphotyrosine-dependent Protein Interaction Screen Reveals a Role for Phosphorylation of Caveolin-1 on Tyrosine 14

Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.

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Phosphorylation-Dependent Protein Interaction with Trypanosoma brucei 14-3-3 Proteins that Display Atypical Target Recognition

PLoS ONE ◽

10.1371/journal.pone.0015566 ◽

2010 ◽

Vol 5 (12) ◽

pp. e15566 ◽

Cited By ~ 5

Author(s):

Masahiro Inoue ◽

Kouichi Yasuda ◽

Haruki Uemura ◽

Natsumi Yasaka ◽

Hiroshi Inoue ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Protein Interaction ◽

Target Recognition ◽

Dependent Protein

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c-Abl is required for oxidative stress-induced phosphorylation of caveolin-1 on tyrosine 14

Cellular Signalling ◽

10.1016/s0898-6568(02)00090-6 ◽

2003 ◽

Vol 15 (3) ◽

pp. 289-298 ◽

Cited By ~ 66

Author(s):

Amy R. Sanguinetti ◽

Cynthia Corley Mastick

Keyword(s):

Oxidative Stress ◽

Caveolin 1 ◽

Tyrosine 14

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Age-Related Increase in Caveolin-1 Expression Facilitates Cell-to-Cell Transmission of α-Synuclein in Neurons

10.21203/rs.3.rs-71594/v4 ◽

2021 ◽

Author(s):

Tae-Young Ha ◽

Yu Ree Choi ◽

Hye Rin Noh ◽

Seon-Heui Cha ◽

Jae-Bong Kim ◽

...

Keyword(s):

Risk Factor ◽

Inclusion Bodies ◽

Aging Process ◽

Caveolin 1 ◽

Age Related ◽

Cell Transmission ◽

Tyrosine 14 ◽

The Relationship ◽

The Brain ◽

Related Increase

Abstract Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

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Caveolin‐1 phosphorylation on tyrosine 14 affects neuronal growth

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.693.11 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Suzanne E Rohrback ◽

Hemal H Patel ◽

Piyush M Patel ◽

Brian P Head

Keyword(s):

Neuronal Growth ◽

Caveolin 1 ◽

Tyrosine 14

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Age-related increase in caveolin-1 expression facilitates cell-to-cell transmission of α-synuclein in neurons

10.21203/rs.3.rs-102606/v1 ◽

2020 ◽

Author(s):

Tae-Young Ha ◽

Yu Ree Choi ◽

Hye Rin Noh ◽

Seon-Heui Cha ◽

Jae-Bong Kim ◽

...

Keyword(s):

Lewy Body ◽

Inclusion Bodies ◽

Primary Neurons ◽

Caveolin 1 ◽

Age Related ◽

Microfluidic Chamber ◽

Cell Transmission ◽

Tyrosine 14 ◽

The Relationship ◽

The Brain

Abstract Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we explored the association between cav-1 and cell-to-cell transmission of α-syn.Methods: Using SH-SY5Y cells and primary neurons overexpressing WT and Y14A cav-1, we investigated the effect of cav-1 expression on the uptake of α-syn using a dual chamber system. Additionally, we investigated the effect of cav-1 expression on the formation of Lewy body-like inclusions using co-culture assay and microfluidic chamber assay.Results: We demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. Conclusions: This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

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Phosphorylation of Caveolin‐1 Tyrosine 14 Leads to Caveolar Coat Destablilzation, Membrane Invagination and Endocytosis

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.797.1 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Adriana Zimnicka ◽

Yawer Husain ◽

Ayesha Shajahan ◽

Peter Toth ◽

Richard Minshall

Keyword(s):

Caveolin 1 ◽

Membrane Invagination ◽

Tyrosine 14

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Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood–brain barrier

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18822801 ◽

2019 ◽

Vol 40 (2) ◽

pp. 420-436 ◽

Cited By ~ 5

Author(s):

Yutaro Hoshi ◽

Yasuo Uchida ◽

Masanori Tachikawa ◽

Sumio Ohtsuki ◽

Pierre-Olivier Couraud ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Brain Barrier ◽

Ischemia Reperfusion ◽

Rapid Decrease ◽

Brain Barrier ◽

Efflux Transport ◽

Caveolin 1 ◽

Abl Kinase ◽

P Glycoprotein ◽

Tyrosine 14

Exposure of the brain to high levels of glucocorticoids during ischemia–reperfusion induces neuronal cell death. Oxidative stress alters blood–brain barrier (BBB) function during ischemia–reperfusion, and so we hypothesized that it might impair P-glycoprotein (P-gp)-mediated efflux transport of glucocorticoids at the BBB. Therefore, the purpose of this study was to clarify the molecular mechanism of this putative decrease of P-gp-mediated efflux function. First, we established that H2O2 treatment of a human in vitro BBB model (hCMEC/D3) reduced both P-gp efflux transport activity and protein expression on the plasma membrane within 20 min. These results suggested that the rapid decrease of efflux function might be due to internalization of P-gp. Furthermore, H2O2 treatment markedly increased tyrosine-14-phosphorylated caveolin-1, which is involved in P-gp internalization. A brain perfusion study in rats showed that cortisol efflux at the BBB was markedly decreased by H2O2 administration, and inhibitors of Abl kinase and Src kinase, which phosphorylate tyrosine-14 in caveolin-1, suppressed this decrease. Overall, these findings support the idea that oxidative stress-induced activation of Abl kinase and Src kinase induces internalization of P-gp via the phosphorylation of tyrosine-14 in caveolin-1, leading to a rapid decrease of P-gp-mediated cortisol efflux at the BBB.

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