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The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras
Shigeaki Sawada1, Mitsunori Yoshimoto, Elena Odintsova
1Cancer Research UK Institute for Cancer Studies and School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom.
Abstract:
Transmembrane proteins of the tetraspanin superfamily are associated with integrins and are thought to regulate adhesion-dependent signaling. The molecular mechanisms of this regulation remain unknown. We used rat fibroblasts to analyze the contribution of the tetraspanin CD151 in the adhesion-dependent signaling. Expression of CD151 specifically attenuated adhesion-dependent activation of Ras. Furthermore, activation of PKB/c-Akt and ERK1/2, downstream targets in the Ras signaling pathway, was also diminished in cells expressing CD151. In contrast, adhesion-dependent activation of FAK and c-Src were not affected by CD151. The attenuation of Ras signaling did not correlate with phosphorylation of Tyr925-FAK, tyrosine phosphorylation of Shc, or with assembly of the p120RasGAP-p62Dok complex. Using mutants of CD151 we established that the cytoplasmic C-terminal portion is critical for activity of CD151 toward Ras. Taken together these results identify CD151 as a negative regulator of Ras and suggest a novel mechanism of adhesion-dependent regulation of Ras activity.
Insights
Tetraspanin CD151 negatively regulates Ras signaling. This study reveals CD151
Area of Science:
- Cellular signaling
- Molecular biology
- Protein interactions
Background:
- Tetraspanin proteins, including CD151, interact with integrins.
- Their role in regulating adhesion-dependent signaling is established, but molecular mechanisms are unclear.
Purpose of the Study:
- To investigate the role of tetraspanin CD151 in adhesion-dependent signaling.
- To elucidate the molecular mechanisms by which CD151 influences signaling pathways.
Main Methods:
- Utilized rat fibroblasts to study CD151 function.
- Analyzed adhesion-dependent activation of key signaling molecules (Ras, PKB/c-Akt, ERK1/2, FAK, c-Src).
- Employed CD151 mutants to identify critical functional domains.
Main Results:
- CD151 expression attenuated adhesion-dependent Ras activation.
- Downstream signaling molecules PKB/c-Akt and ERK1/2 activation were diminished.
- Adhesion-dependent activation of FAK and c-Src remained unaffected by CD151.
- The C-terminal cytoplasmic portion of CD151 is crucial for its effect on Ras.
Conclusions:
- CD151 acts as a negative regulator of Ras signaling.
- Identified a novel mechanism for adhesion-dependent regulation of Ras activity involving CD151.