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Published on: November 29, 2016
Csk regulates integrin-mediated signals: involvement of differential activation of ERK and Akt
Jianguo Gu1, Shigeyuki Nada, Masato Okada
1Division of Protein Chemistry, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan. jgu@protein.osaka-u.ac.jp
Abstract:
Csk phosphorylates Src family tyrosine kinases and down-regulates their activities in vitro and in vivo. To gain insight into the integrin-mediated cellular functions of this negative regulator of the Src family, we examined integrin-mediated signals in Csk-deficient fibroblasts (Csk(-) cells) and their stable transfectants expressing re-introduced Csk (Csk(-)/Csk cells). Integrin-mediated activation of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase in Csk(-)/Csk cells upon adhesion to fibronectin or laminin-10/11 was down-regulated, whereas Akt activation increased. Interestingly, the suppression of ERK-MAP kinase activation in Csk(-)/Csk cells was restored by overexpression of a dominant-negative Akt. In agreement with these results, Csk(-)/Csk cells were more resistant to apoptosis induced by serum depletion, but were less proliferative, compared with Csk(-) cells. These results, taken together, demonstrate that Csk is an important regulator of integrin-mediated signaling and cellular behavior.
Insights
Csk protein regulates cell signaling pathways involved in cell adhesion and survival. Its absence affects extracellular signal-regulated kinase/mitogen-activated protein kinase and Akt activation, impacting cell proliferation and apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Csk (C-terminal Src kinase) is a known negative regulator of Src family tyrosine kinases.
- Integrins are cell surface receptors crucial for cell adhesion and signaling.
Purpose of the Study:
- To investigate the role of Csk in integrin-mediated signaling pathways.
- To understand how Csk deficiency affects cellular behaviors like proliferation and apoptosis.
Main Methods:
- Utilized Csk-deficient fibroblasts and stable transfectants re-expressing Csk.
- Analyzed integrin-mediated activation of ERK/MAP kinase and Akt signaling.
- Assessed cellular responses including apoptosis and proliferation.
Main Results:
- Csk deficiency altered integrin-mediated signaling, decreasing ERK/MAP kinase activation and increasing Akt activation.
- Overexpression of dominant-negative Akt partially restored ERK/MAP kinase signaling.
- Csk-deficient cells showed increased resistance to apoptosis but reduced proliferation.
Conclusions:
- Csk plays a significant role in regulating integrin-mediated signaling pathways.
- Csk influences cellular behaviors, including apoptosis and proliferation, through modulation of key signaling molecules.
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