PMC

Classification of protein phosphatase superfamilies. Protein phosphatases were first classified into six different families according to the catalytic domain InterPro annotation (1). Next each phosphatase family was further subdivided into different classes according to their preferred substrates (2) or literature annotation (3). The number of phosphatases in each family or class is in parenthesis.

Sequence similarity tree of the phosphatase catalytic domains. The tree illustrates the sequence similarity of domain families that do not have a common ancestor and should not be interpreted as an evolutionary tree. The phosphatase names are colored according to the classification in and the classification of phosphatase catalytic domain. The tree chart was created by the FigTree software using as input a multiple sequence alignment, generated by ClustalW2 software using a PAM protein weight matrix, a 25 gap open penalty value and a 0.20 gap extension penalty value.

The human phosphatase interactome. (A) Graph representation of the human phosphatase interactome. 2496 protein–protein interaction pairs involving one of the phosphatase proteins were retrieved from the HomoMINT and IntAct databases . The network was generated with the Cytoscape graphic software. Squared nodes represent phosphatases, while rounded grey nodes represent their targets. The phosphatase color code reflects class affiliation according to the color code convention used throughout this review. Interactors (circles) of “cancer PTPs” whose biological process is not annotated in UniProtKB with GO terms (B) PTPRG-B, (C) PTPN3, (D) PTPRA and (E) DUSP1) were extracted from the global phosphatase interactome and marked in different colors, according to their functional association with GO-Biological Process terms. The phosphatase square nodes are labeled with sectors whose color matches that of the GO-Biological Process term that was significantly overrepresented in the phosphatase interactors and substrates (p-value < 0.002). Edges are colored according to the functional relationships between the nodes they connect: physical associations, dephosphorylations in red and phosphorylation reactions in green and blue respectively. Continuous and dashed lines represent direct (demonstrated in vitro with purified proteins) and indirect dephosphorylation (demonstrated in vivo), respectively.

Accessory module organization in the phosphatase proteins. (A) Cartoon of substrate recognition via three main strategies. Module-based: the catalytic domain is fused to an accessory domain that targets the substrate; SLiM-mediated: the phosphatase contains one (or more) short linear motif (SLiM), which is recognized by a binding domain in the substrate; Regulatory Subunit-assisted: the catalytic and the targeting domains are in separate chains and act in concert to target substrate dephosphorylation. (B) The nodes in the graph representation indicate different domain architectures, that is, proteins that have the same domain composition. Node size is proportional to the class member-count, node color matches the classification of class members according to the legend in the lower part of the Figure. Red borders identify classes containing at least a protein interaction domain. Domain architecture classes that share one domain are linked with an edge labeled with the shared domain.