Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2008) Nucleic Acids Res , doi:10.1093/nar/gkn808

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VHS Domain present in VPS-27, Hrs and STAM

There are 373 VHS domains in 373 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a VHS domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with VHS domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Cellular role: signalling, transport
  

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Lohi O, Lehto VP
  • 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.

  • Asao H et al.
  • 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
  • Display abstract

  • 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.

  • Takeshita T et al.
  • 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
  • Display abstract

  • 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.

  • Takeshita T et al.
  • Cloning of a novel signal-transducing adaptor molecule containing an SH3 domain and ITAM.
  • Biochem Biophys Res Commun. 1996; 225: 1035-9
  • Display abstract

  • 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.

  • Komada M, Kitamura N
  • 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)

• % proteins involved KEGG pathway ID Description 100.00 map04630 Jak-STAT signaling pathway 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%.

• Structure (3D structures containing this domain)

• 3D Structures of VHS domains in PDB

  PDB code	Main view	Title
  1dvp		Crystal structure of the vhs and fyve tandem domains of hrs, a protein involved in membrane trafficking and signal transduction
  1elk		Vhs domain of tom1 protein from h. sapiens
  1jpl		Gga3 vhs domain complexed with c-terminal peptide from cation-independent mannose 6-phosphate receptor
  1juq		Gga3 vhs domain complexed with c-terminal peptide from cation-dependent mannose 6-phosphate receptor
  1jwf		Crystal structure of human gga1 vhs domain.
  1jwg		Vhs domain of human gga1 complexed with cation-independent m6pr c-terminal peptide
  1lf8		Complex of gga3-vhs domain and ci-mpr c-terminal phosphopeptide
  1mhq		Crystal structure of human gga2 vhs domain
  1py1		Complex of gga1-vhs domain and beta-secretase c-terminal phosphopeptide
  1ujj		Vhs domain of human gga1 complexed with c-terminal peptide from bace
  1ujk		Vhs domain of human gga1 complexed with c-terminal phosphopeptide from bace
  1vdy		Nmr structure of the hypothetical enth-vhs domain at3g16270 from arabidopsis thaliana
  1x5b		The solution structure of the vhs domain of human signal transducing adaptor molecule 2
  2dcp		Fully automated nmr structure determination of the enth-vhs domain at3g16270 from arabidopsis thaliana

• Links (links to other resources describing this domain)

• PFAM	VHS
  INTERPRO	IPR002014