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Eps15: a multifunctional adaptor protein regulating intracellular traffickingAbstract: Receptor tyrosine kinases (RTK) are a large family of signaling proteins involved in a large number of human diseases. They all have a similar composition: an extracellular domain that binds to a growth factor, a trans-membrane domain, an intracellular tyrosine kinase domain and a stretch of tyrosine residues that serves as substrates for the kinase. Binding of the growth factor results in kinase activation and consequently in the trans-phosphorylation of the receptor, as well as of various effector molecules resulting in the stimulation of a large number of signaling cascades. One of the most studied RTKs is the epidermal growth factor (EGF) receptor (EGFR or ErbB1), which belongs to a family of four related receptor tyrosine kinases (ErbB1-4 or Her1-4)). EGFR and its family members are strongly implicated in the development and progression of different human tumors, including breast-, lung-, prostate-, colorectal-, head and neck- and brain tumors [1]. These cancers are often correlated with receptor over-expression and/or mutations in the receptor tyrosine kinase, frequently associated with poor prognosis for patients [2].Attenuation of RTK signaling is governed by several mechanisms. At the receptor level, tyrosine phosphatases reduce the number of phosphorylated tyrosine residues. At the cellular level, inhibition of signaling is accomplished by receptor desensitization or down regulation. This process involves the internalization of active ligand/receptor complexes and subsequent trafficking to lysosomes, where receptors are degraded [3]. Ubiquitination of the RTKs is considered as an important step both in the recruitment of receptors into coated pits and in the sorting process in the early endosome [4,5]. Aberrant expression of regulators of endocytosis and consequently of receptor down regulation is strongly related to the development of many different cancers [6]. For instance, abolishment of the ubiquitination of EGFR by mutations in the involved E3 ligase
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