Domains, Motifs, and Scaffolds: The Role of Modular Interactions in the Evolution and Wiring of Cell Signaling Circuits

Bhattacharyya, Roby P.; Reményi, Attila; Yeh, Brian J.; Lim, Wendell A.

doi:10.1146/annurev.biochem.75.103004.142710

Cited by 414 publications

(422 citation statements)

References 163 publications

(109 reference statements)

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“…On the one hand, protein X might be phosphorylated without any offtarget activity thanks to mechanisms that increase the specificity of kinase-protein interactions and phosphorylation [51]. This is for instance achieved by subcellular organization of kinase and phosphatase complexes with their substrates via scaffold and adaptor proteins [52,53]. On the other hand, the kinase(s) responsible for the phosphorylation of X may also randomly encounter other proteins within its subcellular compartment and, further, many kinases are active in more than one compartment [36].…”

Section: Introduction (A)mentioning

confidence: 99%

Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information

Levy

Michnick

Landry

2012

Phil. Trans. R. Soc. B

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In eukaryotic cells, protein phosphorylation is an important and widespread mechanism used to regulate protein function. Yet, of the thousands of phosphosites identified to date, only a few hundred at best have a characterized function. It was recently shown that these functional sites are significantly more conserved than phosphosites of unknown function, stressing the importance of considering evolutionary conservation in assessing the global functional landscape of phosphosites. This leads us to review studies that examined the impact of phosphorylation on evolutionary conservation. While all these studies have shown that conservation is greater among phosphorylated sites compared with non-phosphorylated ones, the magnitude of this difference varies greatly. Further, not all studies have considered key factors that may influence the rate of phosphosite evolution. Such key factors are their localization in ordered or disordered regions, their stoichiometry or the abundance of their corresponding protein. Here we take into account all of these factors simultaneously, which reveals remarkable evolutionary patterns. First, while it is well established that protein conservation increases with abundance, we show that phosphosites partly follow an opposite trend. More precisely, Saccharomyces cerevisiae phosphosites present among abundant proteins are 1.5 times more likely to diverge in the closely related species Saccharomyces bayanus when compared with phosphosites present in the 5 per cent least abundant proteins. Second, we show that conservation is coupled to stoichiometry, whereby sites frequently phosphorylated are more conserved than those rarely phosphorylated. Finally, we provide a model of functional and noisy or 'accidental' phosphorylation that explains these observations.

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Section: Introduction (A)mentioning

confidence: 99%

Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information

Levy

Michnick

Landry

2012

Phil. Trans. R. Soc. B

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“…Scaffold proteins organize functional complexes and modulate kinase activities, thereby contributing to accurate coordination of signaling pathways (Bhattacharyya et al, 2006). Abnormal expression of scaffold proteins has been linked to different types of cancer in human (Claperon and Therrien, 2007).…”

Section: Introductionmentioning

confidence: 99%

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

et al. 2011

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Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.

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“…23 In essence, a complicated cellular sorting/trafficking and assembly system, made up of membranous organelles, receptors, membrane translocation devices, cytoskeletal tracks, motor proteins, and accessory chaperones guides the proper compartmentalization, localization, and assembly of proteins in the cell. [24][25][26] Here, we show that in the absence of energy even this well developed infrastructure would be insufficient to account for the generation of the interactome, which requires a continuous expenditure of energy to maintain steady state.…”

Section: Hierarchic Assembly Of the Interactomementioning

confidence: 83%

The Levinthal paradox of the interactome

Tompa

Rose

2011

Protein Science

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The central biological question of the 21st century is: how does a viable cell emerge from the bewildering combinatorial complexity of its molecular components? Here, we estimate the combinatorics of self-assembling the protein constituents of a yeast cell, a number so vast that the functional interactome could only have emerged by iterative hierarchic assembly of its component sub-assemblies. A protein can undergo both reversible denaturation and hierarchic self-assembly spontaneously, but a functioning interactome must expend energy to achieve viability. Consequently, it is implausible that a completely ''denatured'' cell could be reversibly renatured spontaneously, like a protein. Instead, new cells are generated by the division of pre-existing cells, an unbroken chain of renewal tracking back through contingent conditions and evolving responses to the origin of life on the prebiotic earth. We surmise that this nondeterministic temporal continuum could not be reconstructed de novo under present conditions.

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Domains, Motifs, and Scaffolds: The Role of Modular Interactions in the Evolution and Wiring of Cell Signaling Circuits

Cited by 414 publications

References 163 publications

Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information

Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

The Levinthal paradox of the interactome

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