Whose operations need to be coordinated for the execution of certain cellular processes. The deconvolution of the complete physical and functional wiring of these “local” networks is facilitated by their limited extension, and can potentially reveal elements of the higher level of organization and hierarchy of basic cellular functions. The high throughput screening cost EH-network represents a case in point. This network is established through the EH domain, a protein:protein interaction module originally identified, in three copies, in the endocytic Tofacitinib proteins eps15 and eps15R. A variety of approaches identified three classes of EH-binding peptides. The majority of EH domains bind preferentially to NPF containing peptides, or to variants thereof. In keeping with these results, several proteins that specifically interact with EH domains have been identified; all possess NPF motifs and class III, although it is not completely clear whether these motifs represent true physiological binders or peptidomimetics. EH domains are also able to bind to phosphatidylinositols. One appealing feature of the EH-network is its limited size. There are eleven EH-containing proteins in the human genome, grouped into 5 families, and these are conserved from nematodes to mammals. The domain is also present in yeast. Many studies have been directed at understanding the physiological role of the EH network. The combined analysis of the properties of EH-containing proteins and of the cellular proteins that interact with them allows us to extrapolate some general concepts, which point to the EH-network as an integrator of signaling pathways. First, the majority of the EHnetwork proteins have established functions at various steps of the endocytic route and in the process of synaptic vesicle recycling. Second, some EH-network proteins participate in other events of intracellular traffic, for example, c-synergin is involved in Golgi to endosome trafficking. Third, EH-network proteins are also involved in the organization of the actin cytoskeleton. Finally, a number of EH-containing and EH-interacting proteins shuttle in and out of the nucleus, where they might participate in the control of transcription or of other nuclear events. In summary, the EH network appears to integrate several physiological functions and its subversion is involved in relevant pathological conditions, including cancer. The limited extension of the EH-network makes it an attractive protein:protein network for high-resolution physical and functional mapping at an organismal level. We chose the nematode C. elegans as a model system because, in addition to its genetic tractability, which is paramount for functional studies, C. elegans possesses only five EH-containing proteins, representative of each of the five mammalian EH families: the Eps15, Intersectin, EHD, Reps and c-synergin families. Thus, the nematode EHnetwork can be considered a simplified “prototypical” version of its mammalian counterpart. Lower organisms, such as S. cerevisiae, do not possess all orthologues of mammalian EH-containing proteins, thus reinforcing the idea that C. elegans is the simplest model system that can be used to obtain information that can be extrapolated to mammalian physiology. In this paper, we report the physical and functional 
wiring of the EH network, at the organismal level, in the nematode.