have suggested a protective role of SARA in skin carcinogenesis, showing that SARA is not involved either in the activation process of TGF-β signal transduction or mouse development. Interestingly, SARA also interacts with ubiquitin ligase RNF11, participates structurally and functionally in the ESCRT (endosomal sorting complexes requi red for transport) and regulates degradative EGFR trafficking. These alterations resemble the defects caused by overexpression of the Rab5 mutant (Rab5Q79L) and suggest that SARA plays an important functional role downstream of Rab5-regulated endosomal trafficking. For example, it has been shown that SARA overexpression causes enlargement of EE, and significantly delays transferrin recycling. These data suggest that SARA may regulate other events. Moreover, knockdown of SARA in HeLa cells does not interfere with TGFβ-induced Smad activation, Smad nuclear translocation, or induction of TGFβ target genes. Recent data suggests that SARA is dispensable for functional TGFβ-mediated signaling, because in various B-cell lymphomas no correlation was found between SARA expression and the levels of TGFβ-induced phosphorylation of Smads. The FYVE domain directs the ligand TGFβ to EE, where it interacts with both TGFβ receptors and Smads. It has been suggested that SARA has a crucial function in the recruitment of Smad to the TGFβ receptor, ensuring appropriate subcellular localization of the activated receptor-bound complex. SARA also contains a Smad-binding domain (SBD) required for the interaction with the transcription factors Smad2 and Smad3 and a C-terminal region that interacts with the type I TGFβ receptor (TGFβ-RI). SARA is a FYVE protein ( Fab1, YOTB, Vac1 and EEA1, ) that binds to PI3P ( phosphatidyl inositol 3- phosphate), is highly enriched in endocytic membranes and is involved in membrane trafficking. Dysfunction of proteins involved in endocytic trafficking has been linked to the development of neurodegenerative diseases, implicating at the membrane trafficking control machinery as a critical factor in neuron function. In neurons, the regulation of endosomal trafficking is particularly complex, since the generation of asymmetric domains requires specialized membrane trafficking not only to promote neurite outgrowth but also to ensure differential distribution of components to the axonal or somatodendritic domains. Neurons are among the best examples of polarized cells, having two functionally different structural domains: a single long axon, and multiple short highly branched dendrites. The endosomal pathway is known to play a decisive role in many neurodevelopment processes, including migration, polarization and synaptic function. The fate of the endocytic cargo is determined by the activity and molecular nature of the endosomal sorting machinery. After internalization, a cargo is transported to early endosomes (EE) where sorting decisions are made : proteins targeted for degradation shift to late endosomes and lysosomes, whereas proteins recycled to the cell surface through recycling endosomes (RE) are subject to slow recycling, or fast recycling if travelling directly from early endosomes for later reinsertion into the plasma membrane. This requires significant coordination between spatially segregated sorting compartments that function to determine the cellular fate of cargos. In mammal cells, endocytic membrane traffic plays an essential role in delivering membrane components, receptor-associated ligands and solute molecules to intracellular destinations.
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