Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.
The ADAM family consists of a number of transmembrane proteins that contain disintegrin-like and metalloproteinase-like domains. Therefore, ADAMs potentially have cell adhesion and protease activities. 14-3-3 proteins are a highly conserved family of cytoplasmic proteins that associate with several intracellular signaling molecules in the regulation of various cellular functions. Here we report the identification of a novel interaction between the ADAM 22 cytoplasmic tail and the 14-3-3zeta isoform by a yeast two-hybrid screen. The interaction between the ADAM 22 cytoplasmic tail and 14-3-3zeta was confirmed by an in vitro protein pull-down assay as well as by co-immunoprecipitation, and the binding sites were mapped to the 28 amino acid residues of the C-terminus of the ADAM 22 cytoplasmic tail. Furthermore, we found that overexpression of the ADAM 22 cytoplasmic tail in human SGH44 cells inhibited cell adhesion and spreading and that deletion or mutation of the binding site for 14-3-3zeta within the ADAM 22 cytoplasmic tail abolished the ability of the overexpressed cytoplasmic tail to alter cell adhesion and spreading. Taken together, these results for the first time demonstrate an association between ADAM 22 and a 14-3-3 protein and suggest a potential role for the 14-3-3zeta/ADAM 22 association in the regulation of cell adhesion and related signaling events.
OBJECTIVE: To study the expression and function of the brain-specific proteinase deficient disintegrins, ADAM11 and ADAM22 (a disintegrin and metalloproteinase). METHODS: Specimens of low- and high-grade gliomas and normal brain were analyzed for ADAM11 and ADAM22 expression using Western blotting. The effects of overexpression of ADAM11 and ADAM22 in glioma cells on growth were analyzed using bromodeoxyuridine incorporation linked to immunocytochemistry. Similarly analyzed were the effects on cell proliferation of bacterially expressed glutathione S-transferase fusion proteins with the disintegrin domain of ADAM11 and ADAM22. RESULTS: ADAM22 is expressed in normal brain and some low-grade gliomas, but not in high-grade gliomas, whereas ADAM11 is expressed in all low- and high-grade gliomas. In vitro, ADAM22 inhibits cellular proliferation of glioma derived astrocytes. The growth inhibition appears to be mediated by interactions between the disintegrin domain of ADAM22 and specific integrins expressed on the cell surface. This growth inhibition can be avoided by over-expression of integrin linked kinase. CONCLUSION: ADAM22, a brain-specific cell surface protein, mediates growth inhibition using an integrin dependent pathway. It is expressed in normal brain but not in high-grade gliomas. A related protein, ADAM11, has only a minor effect on cell growth, and its expression is unchanged in low- and high-grade gliomas.
Cellular adhesion plays important roles in a variety of biological processes. The ADAM family contains disintegrin-like and metalloproteinase-like domains which potentially have cell adhesion and protease activities. Recent studies suggest that the interaction between 14-3-3zeta and ADAM22cyt can regulate cell adhesion and spreading, therefore it has a potential role in neural development and function. 14-3-3 family has seven highly conserved members that regulate various cellular functions. Using yeast two-hybrid method, we identified that ADAM22cyt bound some other 14-3-3 family members. The interaction was further confirmed by in vitro protein pull-down assay and co-immunoprecipitation. We also found that the overexpression of exogenous ADAM22 in HEK293 cells could significantly enhance cell adhesion and spreading, compared with the truncated ADAM22 lack of 14-3-3 binding motifs. These results strongly demonstrated a functional role for ADAM22/14-3-3 in cell adhesion and spreading.
Biochem. J. 334 ( Pt 1), 93-98 (1998)[PubMed:9693107]
Cellular disintegrins are a family of membrane-anchored proteins structurally related to snake venom disintegrins, and are potential regulators of cell-cell and cell-matrix interactions. The members of this protein family are also called ADAMs (a disintegrin and metalloproteinase) or MDC proteins (metalloproteinase-like disintegrin-like cysteine-rich), because they all contain disintegrin-like and metalloproteinase-like domains. In this paper, we report the cloning and sequence analysis of two novel additional members of this family, which we have termed MDC2 and MDC3. The deduced amino acid sequences reveal that the two proteins possess typical cellular disintegrin structures [that is, pro-, metalloproteinase-like, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains] and exhibit high sequence similarity with human MDC/ADAM11 protein [Katagiri, Harada, Emi and Nakamura (1995) Cytogenet. Cell Genet. 68, 39-44]. A zinc-binding motif, which is critical for proteinase activity, is disrupted in the metalloproteinase-like domain of MDC2 and MDC3, as well as MDC/ADAM11. In the disintegrin-like domain of snake venom short disintegrins, the RDG-containing loops are critical for integrin binding. These three MDCs do not contain the RDG sequences, but the corresponding loops in these proteins are similar to each other. Northern blot analysis revealed that the mRNAs of MDC2, MDC3 and MDC/ADAM11 are highly expressed in the brain. These findings suggest that these proteins may function as integrin ligands in the brain.
Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a mechanism in which water acts as a nucleophile, one or two metal ions hold the water molecule in place, and charged amino acid side chains are ligands for the metal ions.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionDFLAT
Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.
Evidence
2:
Inferred from Physical InteractionIntAct
Evidence for Iso 3
ADAM22 is one of three catalytically inactive ADAM family members highly expressed in the brain. ADAM22 has numerous splice variants, all with considerable cytoplasmic tails of up to 148 amino acids. ADAM22 can act to inhibit cell proliferation, however, it has been suggested that it also acts as an adhesion protein. We identified three 14-3-3 protein members by a yeast two-hybrid screen and show by co-immunoprecipitation that the cytoplasmic domain of ADAM22 can interact with all six 14-3-3 proteins expressed in the brain. In addition, we show that 14-3-3 proteins interact preferentially with the serine phosphorylated precursor form of ADAM22. ADAM22 has two 14-3-3 protein binding consensus motifs; the first binding site, spanning residues 831-834, was shown to be the most crucial for 14-3-3 binding to occur. The interaction between ADAM22 and 14-3-3 proteins is dependent on phosphorylation of ADAM22, but not of 14-3-3 proteins. ADAM22 point mutants lacking functional 14-3-3 protein binding motifs could no longer accumulate efficiently at the cell surface. Deletion of both 14-3-3 binding sites and newly identified ER retention motifs restored localization of ADAM22 at the cell surface. These results reveal a role for 14-3-3 proteins in targeting ADAM22 to the membrane by masking ER retention signals.
The process whose specific outcome is the progression of the central nervous system over time, from its formation to the mature structure. The central nervous system is the core nervous system that serves an integrating and coordinating function. In vertebrates it consists of the brain, spinal cord and spinal nerves. In those invertebrates with a central nervous system it typically consists of a brain, cerebral ganglia and a nerve cord.
Biochem. J. 334 ( Pt 1), 93-98 (1998)[PubMed:9693107]
Cellular disintegrins are a family of membrane-anchored proteins structurally related to snake venom disintegrins, and are potential regulators of cell-cell and cell-matrix interactions. The members of this protein family are also called ADAMs (a disintegrin and metalloproteinase) or MDC proteins (metalloproteinase-like disintegrin-like cysteine-rich), because they all contain disintegrin-like and metalloproteinase-like domains. In this paper, we report the cloning and sequence analysis of two novel additional members of this family, which we have termed MDC2 and MDC3. The deduced amino acid sequences reveal that the two proteins possess typical cellular disintegrin structures [that is, pro-, metalloproteinase-like, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains] and exhibit high sequence similarity with human MDC/ADAM11 protein [Katagiri, Harada, Emi and Nakamura (1995) Cytogenet. Cell Genet. 68, 39-44]. A zinc-binding motif, which is critical for proteinase activity, is disrupted in the metalloproteinase-like domain of MDC2 and MDC3, as well as MDC/ADAM11. In the disintegrin-like domain of snake venom short disintegrins, the RDG-containing loops are critical for integrin binding. These three MDCs do not contain the RDG sequences, but the corresponding loops in these proteins are similar to each other. Northern blot analysis revealed that the mRNAs of MDC2, MDC3 and MDC/ADAM11 are highly expressed in the brain. These findings suggest that these proteins may function as integrin ligands in the brain.
The process in which neuronal axons and dendrites become coated with a segmented lipid-rich sheath (myelin) to enable faster and more energetically efficient conduction of electrical impulses. The sheath is formed by the cell membranes of Schwann cells in the peripheral nervous system. Adjacent myelin segments are separated by a non-myelinated stretch of axon called a node of Ranvier.
Biochem. J. 334 ( Pt 1), 93-98 (1998)[PubMed:9693107]
Cellular disintegrins are a family of membrane-anchored proteins structurally related to snake venom disintegrins, and are potential regulators of cell-cell and cell-matrix interactions. The members of this protein family are also called ADAMs (a disintegrin and metalloproteinase) or MDC proteins (metalloproteinase-like disintegrin-like cysteine-rich), because they all contain disintegrin-like and metalloproteinase-like domains. In this paper, we report the cloning and sequence analysis of two novel additional members of this family, which we have termed MDC2 and MDC3. The deduced amino acid sequences reveal that the two proteins possess typical cellular disintegrin structures [that is, pro-, metalloproteinase-like, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains] and exhibit high sequence similarity with human MDC/ADAM11 protein [Katagiri, Harada, Emi and Nakamura (1995) Cytogenet. Cell Genet. 68, 39-44]. A zinc-binding motif, which is critical for proteinase activity, is disrupted in the metalloproteinase-like domain of MDC2 and MDC3, as well as MDC/ADAM11. In the disintegrin-like domain of snake venom short disintegrins, the RDG-containing loops are critical for integrin binding. These three MDCs do not contain the RDG sequences, but the corresponding loops in these proteins are similar to each other. Northern blot analysis revealed that the mRNAs of MDC2, MDC3 and MDC/ADAM11 are highly expressed in the brain. These findings suggest that these proteins may function as integrin ligands in the brain.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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