CYLD Inhibits Melanoma Growth and Progression through Suppression of the JNK/AP-1 and β1-Integrin Signaling Pathways

Remodeling of dendritic spines is believed to modulate the function of excitatory synapses. We previously reported that the EphA4 receptor tyrosine kinase regulates spine morphology in hippocampal pyramidal neurons, but the signaling pathways involved were not characterized (Murai, K.K., L.N. Nguyen, F. Irie, Y. Yamaguchi, and E.B. Pasquale. 2003. Nat. Neurosci. 6:153–160). In this study, we show that EphA4 activation by ephrin-A3 in hippocampal slices inhibits integrin downstream signaling pathways. EphA4 activation decreases tyrosine phosphorylation of the scaffolding protein Crk-associated substrate (Cas) and the tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) and also reduces the association of Cas with the Src family kinase Fyn and the adaptor Crk. Consistent with this, EphA4 inhibits β1-integrin activity in neuronal cells. Supporting a functional role for β1 integrin and Cas inactivation downstream of EphA4, the inhibition of integrin or Cas function induces spine morphological changes similar to those associated with EphA4 activation. Furthermore, preventing β1-integrin inactivation blocks the effects of EphA4 on spines. Our results support a model in which EphA4 interferes with integrin signaling pathways that stabilize dendritic spines, thus modulating synaptic interactions with the extracellular environment.

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The involvement of Gab1 and PI 3-kinase in β1 integrin signaling in keratinocytes

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.07.017 ◽

2007 ◽

Vol 361 (1) ◽

pp. 224-229 ◽

Cited By ~ 4

Author(s):

Yoshihiro Kuwano ◽

Manabu Fujimoto ◽

Rei Watanabe ◽

Nobuko Ishiura ◽

Hiroko Nakashima ◽

...

Keyword(s):

Integrin Signaling ◽

Β1 Integrin

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Multi-Omics Analysis to Reveal Disorders of Cell Metabolism and Integrin Signaling Pathways induced by PM2.5

Journal of Hazardous Materials ◽

10.1016/j.jhazmat.2021.127573 ◽

2021 ◽

pp. 127573

Author(s):

Xiaoyao Song ◽

Jianhui Liu ◽

Ningbo Geng ◽

Yichu Shan ◽

Baoqin Zhang ◽

...

Keyword(s):

Signaling Pathways ◽

Cell Metabolism ◽

Integrin Signaling ◽

Omics Analysis

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Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice

Nature Medicine ◽

10.1038/nm.4116 ◽

2016 ◽

Vol 22 (8) ◽

pp. 889-896 ◽

Cited By ~ 89

Author(s):

Michelle Rozo ◽

Liangji Li ◽

Chen-Ming Fan

Keyword(s):

Integrin Signaling ◽

Β1 Integrin ◽

Dystrophic Muscle

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Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner

Molecular Biology of the Cell ◽

10.1091/mbc.e12-02-0132 ◽

2012 ◽

Vol 23 (17) ◽

pp. 3473-3484 ◽

Cited By ~ 37

Author(s):

Mohammed-Amine El Azreq ◽

Dalila Naci ◽

Fawzi Aoudjit

Keyword(s):

Actin Polymerization ◽

Mitogen Activated Protein Kinase ◽

Integrin Signaling ◽

Β1 Integrin ◽

Dependent Manner ◽

Expression Levels ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

And Function

The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly understood. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T-cells by up-regulating the expression and function of the ATP-binding cassette C 1 (ABCC1) transporter, also known as multidrug resistance–associated protein 1. We find that collagen but not fibronectin reduces intracellular doxorubicin content and up-regulates the expression levels of ABCC1. Inhibition and knockdown studies show that up-regulation of ABCC1 is necessary for collagen-mediated reduction of intracellular doxorubicin content and collagen-mediated inhibition of doxorubicin-induced apoptosis. We also demonstrate that activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signaling pathway is involved in collagen-induced reduction of intracellular doxorubicin accumulation, collagen-induced up-regulation of ABCC1 expression levels, and collagen-mediated cell survival. Finally, collagen-mediated up-regulation of ABCC1 expression and function also requires actin polymerization. Taken together, our results indicate for the first time that collagen/β1 integrin/ERK signaling up-regulates the expression and function of ABCC1 and suggest that its activation could represent an important pathway in cancer chemoresistance. Thus simultaneous targeting of collagen/β1 integrin and ABCC1 may be more efficient in preventing drug resistance than targeting each pathway alone.

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Integrin-mediated axoglial interactions initiate myelination in the central nervous system

The Journal of Cell Biology ◽

10.1083/jcb.200807010 ◽

2009 ◽

Vol 185 (4) ◽

pp. 699-712 ◽

Cited By ~ 51

Author(s):

Joana Câmara ◽

Zhen Wang ◽

Cristina Nunes-Fonseca ◽

Hana C. Friedman ◽

Matthew Grove ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Small Diameter ◽

Single Copy ◽

Dominant Negative ◽

Hypoxanthine Phosphoribosyl Transferase ◽

Integrin Signaling ◽

Β1 Integrin ◽

Hprt Locus ◽

The Central Nervous System

All but the smallest-diameter axons in the central nervous system are myelinated, but the signals that initiate myelination are unknown. Our prior work has shown that integrin signaling forms part of the cell–cell interactions that ensure only those oligodendrocytes contacting axons survive. Here, therefore, we have asked whether integrins regulate the interactions that lead to myelination. Using homologous recombination to insert a single-copy transgene into the hypoxanthine phosphoribosyl transferase (hprt) locus, we find that mice expressing a dominant-negative β1 integrin in myelinating oligodendrocytes require a larger axon diameter to initiate timely myelination. Mice with a conditional deletion of focal adhesion kinase (a signaling molecule activated by integrins) exhibit a similar phenotype. Conversely, transgenic mice expressing dominant-negative β3 integrin in oligodendrocytes display no myelination abnormalities. We conclude that β1 integrin plays a key role in the axoglial interactions that sense axon size and initiate myelination, such that loss of integrin signaling leads to a delay in myelination of small-diameter axons.

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