Abstract
Scaffold proteins play a crucial role in facilitating signal transduction in eukaryotes by bringing together multiple signaling components. In this study, we performed a systematic analysis of scaffold proteins in signal transduction by integrating protein-protein interaction and kinase-substrate relationship networks. We predicted 212 scaffold proteins that are involved in 605 distinct signaling pathways. The computational prediction was validated using a protein microarray-based approach. The predicted scaffold proteins showed several interesting characteristics, as we expected from the functionality of scaffold proteins. We found that the scaffold proteins are likely to interact with each other, which is consistent with previous finding that scaffold proteins tend to form homodimers and heterodimers. Interestingly, a single scaffold protein can be involved in multiple signaling pathways by interacting with other scaffold protein partners. Furthermore, we propose two possible regulatory mechanisms by which the activity of scaffold proteins is coordinated with their associated pathways through phosphorylation process.
Highlights
Protein phosphorylation and dephosphorylation is an important means of protein regulation that occur in both prokaryotic and eukaryotic organisms [1,2,3,4,5]
We found that scaffold proteins are likely to form complexes, suggesting that scaffold proteins could participate in diverse signaling pathways through the combinatorial interactions among scaffold proteins
By taking advantage of the existing extensive datasets of protein-protein interactions (PPIs) and kinase-substrate relationships (KSRs), we developed a statistical approach to predict scaffold proteins
Summary
Protein phosphorylation and dephosphorylation is an important means of protein regulation that occur in both prokaryotic and eukaryotic organisms [1,2,3,4,5]. Phosphorylation of a protein may result in a conformational change in its structure, recruitment of binding partners or change of localization, leading to its activation or deactivation [6,7]. In the context of a signaling pathway, a relay of phosphorylation events could allow the transmission of extracellular signals to intracellular targets. One well-known example is the RAS-ERK pathway, in which a small G-protein RAS activates MAP3K RAF, which phosphorylates and activates MAP2K MEK1 (MAPKK1). MEK1 phosphorylates and activates MAPK ERK1/2[8]. Biological systems contain a large number of phosphorylation-related signaling pathways. Many of these signaling pathways share common signaling components and are subject to extensive crossregulation. It is believed that the answer may partially lie in the existence of scaffold proteins
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