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Background
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Cytohesin-4, also known as CYT4 or PSCD4 (pleckstrin homology, Sec7 and coiled-coil domains 4), is a 394 AA ADP-ribosylation factor (ARF) that functions as a guanine nucleotide-exchange protein (GEP) and is expressed primarily in blood leukocytes with minimal expression observed in the thymus and spleen, The newly cloned Cytohesin 4 is a 47 kDa protein with similar structural motifs as in Cytohesin 1, 2 and 3. Cytohesin-4 has a C-terminal pleckstrin homology (PH) domain, an N-terminal coiled-coil motif and a central Sec7 domain. The PH domain is responsible for membrane and phospholipid interaction, while the coiled-coil motif mediates homodimerization. The cytohesin 1 and 4 are very similar except for the 3 base pair (GAG) axon present in Cytohesin 1. The Sec7 domain of Cytohesin-4, wihich is the central domain of the guanosine exchange factors of the ADP-ribosylation factor family of small GTPases, exhibits the GEP activity which, in vitro, can promote guanine nucleotide-exchange with both ARF1 and ARF5 and also promotes the activation of ARF through replacement of GDP with GTP. Over expression of cytohesin 4 stimulated guanosine 5'-3-O-(thio)triphosphate binding to ARF1 and 5 but not to ARF6. The ARFs are approximately 20 kDa GTPases that are inactive in the GDP-bound from but become activated upon binding of GTP via GTP exchange proteins (GEPs). Cytohesins are identified as cytoplasmic ErbB receptor activators in certain cancers, exhibiting an important role in ErbB signaling. Cytohesin overexpression correlated with EGF signaling pathway activation in human lung adenocarcinomas. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, whereas Cytohesin overexpression stimulated receptor activation .
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