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. 2012;7(9):e44882.
doi: 10.1371/journal.pone.0044882. Epub 2012 Sep 13.

Topological and functional properties of the small GTPases protein interaction network

Anna Delprato  1
Affiliations

Topological and functional properties of the small GTPases protein interaction network

Anna Delprato. PLoS One. 2012.

Abstract

Small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) regulate key cellular processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. A great deal of experimental evidence supports the existence of signaling cascades and feedback loops within and among the small GTPase subfamilies suggesting that these proteins function in a coordinated and cooperative manner. The interplay occurs largely through association with bi-partite regulatory and effector proteins but can also occur through the active form of the small GTPases themselves. In order to understand the connectivity of the small GTPases signaling routes, a systems-level approach that analyzes data describing direct and indirect interactions was used to construct the small GTPases protein interaction network. The data were curated from the Search Tool for the Retrieval of Interacting Genes (STRING) database and include only experimentally validated interactions. The network method enables the conceptualization of the overall structure as well as the underlying organization of the protein-protein interactions. The interaction network described here is comprised of 778 nodes and 1943 edges and has a scale-free topology. Rac1, Cdc42, RhoA, and HRas are identified as the hubs. Ten sub-network motifs are also identified in this study with themes in apoptosis, cell growth/proliferation, vesicle traffic, cell adhesion/junction dynamics, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase response, transcription regulation, receptor-mediated endocytosis, gene silencing, and growth factor signaling. Bottleneck proteins that bridge signaling paths and proteins that overlap in multiple small GTPase networks are described along with the functional annotation of all proteins in the network.

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Conflict of interest statement

Competing Interests: The author is a PLoS ONE Editorial Board member. This does not alter her adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. (A) Confidence score distribution.
Plot of the frequency of occurrence vs. the confidence scores for the interaction data used to construct the network. (B) Node degree distribution. Plot of the log10 number of nodes with a given connection vs. the log10 node degrees in the network. The relationship between node number and node degree is described by the regression equation Y = 0,3354 X−1.38 (R2 = 86.0%). (C) Bar plot of the small GTPases that have the greatest number of interactions. Interaction number is labeled above each of the columns. Columns are colored to correspond to the small GTPase subfamilies. Yellow: Rho, Red: Ras, Green: Rab, Purple: Ran, Cyan: Arf. (D) The small GTPases protein interaction network. The graph is shown as a Biolayout (Enright 2001). Color coding for the Small GTPase subfamilies is as described in panel 1C. Non GTPase nodes are colored black. Proteins/nodes are represented as circles and are sized according to the number of connections.
Figure 2
Figure 2. (A) Path length distribution.
Frequency distribution of path lengths for all interactions in the network. (B) Bottlenecks. Cartoon representation of the top 10 bottleneck proteins. Solid lines signify 1st (immediate) neighbor interactions and dotted lines represent 2nd and 3rd (nearest) neighbor interactions respectively, as labeled in the figure. (C) Network motifs. Representative clusters (1, 2, 3, 4, 5, and 10) with biological themes that were identified in the network. The highest scoring (seed) nodes in the cluster are shown as squares.
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