The VHS domain is an about 150 residues long domain, whose name is derived from its occurrence in VPS-27, Hrs and STAM. The VHS domain is found at the N- termini of proteins associated with endocytocis and/or vesicular trafficking, often in association with other domains like FYVE, SH3 or TAM [ (PUBMED:9600884) (PUBMED:9872381) ]. The VHS domain of Hrs makes both intra- and intermolecular interactions with FYVE domains and it has been proposed that it might as well interact with other domains. The VHS domain might function as a multipurpose docking adapter that localizes proteins to the membrane through interactions with the membrane and/or the endocytic machinery [ (PUBMED:10693761) (PUBMED:10985773) ].
Resolution of the crystal structure of the VHS domain of Drosophila Hrs and human Tom1 revealed that it consists of eight helices arranged in a superhelix [ (PUBMED:10693761) (PUBMED:10985773) ].
VHS domain marks a group of proteins involved in endocytosis and vesicular trafficking.
FEBS Lett. 1998; 440: 255-7
Display abstract
Endocytosis is driven by a mechanism which is characterized by an orderly congregation of a large number of proteins which effectuate, first, formation of a coated vesicles, second, pinching off the vesicle and, third, regulated transport. True to the nature of many other proteins involved in multimolecular complexes, also endocytosis-associated proteins, such as Eps15, clathrin and AP-2, are characterized by distinct domains which mediate the protein-protein interactions. We now report that a group of well-established endocytosis and/or vesicular trafficking proteins possess a VHS domain, a recently described domain with an unknown function. We suggest that in these proteins VHS serves as a membrane targeting domain which by its specific features together with FYVE, SH3 and/or TAM domains, which are also present in some VHS-containing proteins, is involved in the stage-specific assembly of the endocytic machinery.
Hrs is associated with STAM, a signal-transducing adaptor molecule. Its suppressive effect on cytokine-induced cell growth.
J Biol Chem. 1997; 272: 32785-91
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We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.
STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction.
Immunity. 1997; 6: 449-57
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We previously identified a putative signal transducing adaptor molecule, named STAM, that contains an Src homology 3 (SH3) domain and immunoreceptor tyrosine-based activation motif (ITAM). In this report, we demonstrate the functional significance of STAM in cytokine-mediated signal transduction. STAM is associated with Jak3 and Jak2 tyrosine kinases via its ITAM region and phosphorylated by Jak3 and Jak2 upon stimulation with IL-2 and GM-CSF, respectively. An SH3 deletion mutant of STAM confers a dominant-negative effect on DNA synthesis mediated by IL-2 and GM-CSF. Furthermore, the wild-type STAM, but not STAM mutants deleted of SH3 and ITAM, significantly enhances c-myc induction mediated by IL-2 and GM-CSF. These results strongly implicate STAM in the signaling pathways for cell growth and c-myc induction immediately downstream of the Jaks associated with the cytokine receptors.
Cloning of a novel signal-transducing adaptor molecule containing an SH3 domain and ITAM.
Biochem Biophys Res Commun. 1996; 225: 1035-9
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We molecularly cloned a cDNA coding for a novel phosphotyrosine molecule with a 70 kDa molecular mass, named STAM (signal transducing adaptor molecule), which is tyrosine-phosphorylated rapidly after stimulation with various cytokines such as IL-2, IL-3, IL-4, IL-7, GM-CSF, EGF and PDGF. STAM contains an SH3 (Src-homology 3) domain and the ITAM (immunoreceptor tyrosine-based activation motif), suggesting that STAM acts as an adaptor molecule involved in signal transducing pathways from the cytokine receptors.
Growth factor-induced tyrosine phosphorylation of Hrs, a novel 115-kilodalton protein with a structurally conserved putative zinc finger domain.
Mol Cell Biol. 1995; 15: 6213-21
Display abstract
The activation of growth factor receptor tyrosine kinases leads to tyrosine phosphorylation of many intracellular proteins which are thought to play crucial roles in growth factor signaling pathways. We previously showed that tyrosine phosphorylation of a 115-kDa protein is rapidly induced in cells treated with hepatocyte growth factor. To clarify the structure and possible function of the 115-kDa protein (designated Hrs for hepatocyte growth factor-regulated tyrosine kinase substrate), we purified this protein from B16-F1 mouse melanoma cells by anti-phosphotyrosine immunoaffinity chromatography and determined its partial amino acid sequences. On the basis of the amino acid sequences, we molecularly cloned the cDNA for mouse Hrs. The nucleotide sequence of the cDNA revealed that Hrs is a novel 775-amino-acid protein with a putative zinc finger domain that is structurally conserved in several other proteins. This protein also contained a proline-rich region and a proline- and glutamine-rich region. The expression of Hrs mRNA was detected in all adult mouse tissues tested and also in embryos. To analyze the Hrs cDNA product, we prepared a polyclonal antibody against bacterially expressed Hrs. Using this antibody, we showed by subcellular fractionation that Hrs is localized to the cytoplasm; we also showed that that tyrosine phosphorylation of Hrs is induced in cells treated with epidermal growth factor or platelet-derived growth factor. These results suggest that Hrs plays a unique and important role in the signaling pathway of growth factors.
Metabolism (metabolic pathways involving proteins which contain this domain)
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VHS domain which could be assigned to a KEGG orthologous group, and not all proteins containing VHS domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
Crystal Structure of the Tandem Vhs and Fyve Domains of Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate (Hgs-Hrs) bound to an IP2 compound at 1.68 A Resolution
Links (links to other resources describing this domain)
