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p70 S6-kinase mediates the cooperation between Akt1 and Mek1 pathways in fibroblast-mediated extracellular matrix

Anna Goc¹, Harika Sabbineni¹, Maha Abdalla¹

¹Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Charlie Norwood VA Medical Center, Augusta, GA, USA.

Biochimica Et Biophysica Acta

|April 7, 2015

Abstract:

Previous studies have demonstrated both synergistic and opposing effects of Akt and Mek1/2 in various cell functions and disease states. Furthermore, Akt has been reported to inhibit and activate cRaf/Mek pathway, suggesting that their mutual interaction and cooperation may be cell type, stimuli and/or context specific. While PI3-kinase/Akt and cRaf/Mek pathways have been implicated in the regulation of extracellular matrix (ECM) remodeling, mutual interactions between these two pathways and their specific contributions to the events leading to ECM synthesis and assembly is not clear. We investigated the specific role of Akt1 and Mek1 in ECM synthesis and assembly by NIH 3T3 fibroblasts and how these effects were reconciled to mediate overall ECM remodeling. Our study identified that cooperation between Akt1 and Mek1 is necessary to mediate ECM synthesis. Whereas Akt1 activation resulted in Mek1 activation as evidenced by increased ERK1/2 phosphorylation, Mek1 inhibition using U0126 or DN-Mek1 resulted in enhanced Akt1 phosphorylation. Interestingly, both Akt1 and Mek1 activities were needed for the synthesis and assembly of ECM. The effect of Akt1 and Mek1 on ECM synthesis was reconciled through the activation of p70 S6-kinase via phosphorylation at T421/S424 and S411, respectively. Furthermore, Akt1 and Mek1 cooperated in mediating ECM assembly via activation of integrin β1. Together, we show for the first time that Akt1 and Mek1 pathways cooperate in the regulation of ECM remodeling by the fibroblasts.

Insights

Cooperation between Akt1 and Mek1 pathways is essential for fibroblast extracellular matrix (ECM) synthesis and assembly, impacting overall ECM remodeling. This study clarifies their synergistic roles in fibroblast-mediated ECM regulation.

Area of Science:

Cell Biology
Biochemistry
Molecular Biology

Background:

Akt and Mek1/2 pathways exhibit complex, context-dependent interactions in cellular functions.
Both pathways are implicated in extracellular matrix (ECM) remodeling, but their specific interplay in ECM synthesis and assembly remains unclear.

Purpose of the Study:

To investigate the distinct roles of Akt1 and Mek1 in fibroblast ECM synthesis and assembly.
To elucidate the cooperative mechanisms between Akt1 and Mek1 in mediating ECM remodeling.

Main Methods:

Utilized NIH 3T3 fibroblasts to study ECM synthesis and assembly.
Employed pharmacological inhibitors (U0126) and dominant-negative constructs (DN-Mek1) to modulate Mek1 activity.
Assessed pathway activation through phosphorylation of key signaling molecules like ERK1/2, Akt1, and p70 S6-kinase.

Main Results:

Akt1 and Mek1 cooperation is necessary for ECM synthesis and assembly in fibroblasts.
Akt1 activation led to Mek1 activation, while Mek1 inhibition enhanced Akt1 phosphorylation, indicating cross-regulation.
Both pathways contribute to ECM synthesis via p70 S6-kinase activation and ECM assembly through integrin β1 activation.

Conclusions:

Akt1 and Mek1 pathways cooperate to regulate ECM synthesis and assembly.
This cooperative interaction is crucial for fibroblast-mediated ECM remodeling.
The findings reveal a novel mechanism of Akt1 and Mek1 pathway synergy in regulating ECM remodeling.

Read full analysis

Keywords:

Akt1 Extracellular matrix Integrin Mek1 mTOR p70 S6-kinase

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