Disease relevance of Dnm1

• Mutations in the dynamin family GTPase OPA1 are reportedly the cause of autosomal dominant optic atrophy, the most frequently occurring form of hereditary optic neuropathy [1].
• To examine the role of clathrin-dependent insulin receptor internalization in insulin-stimulated signal transduction events, we expressed a dominant-interfering mutant of dynamin (K44A/dynamin) by using a recombinant adenovirus in the H4IIE hepatoma and 3T3L1 adipocyte cell lines [2].
• Overexpression of the dynamin K44A dominant negative mutant via an adenovirus expression system induces caveolar invaginations sensitive to methyl-beta-cyclodextrin extraction in the transformed cells without increasing caveolin expression [3].
• Additionally, expression of a dominant-negative form of dynamin I has no effect on polyomavirus uptake and infectivity [4].
• Bafilomycin and dominant-negative dynamin inhibited lipid mixing of Sindbis virus (which requires low pH for fusion), but not of ASLV-A, with host cells [5].

Psychiatry related information on Dnm1

• Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease [6].

High impact information on Dnm1

• Using alternating evanescent field and epifluorescence illumination, we show that CCP invagination and scission are tightly coupled, with scission coinciding with maximal displacement of CCPs from the plasma membrane and with peak recruitment of cortactin-DsRed, a dynamin and F-actin binding protein [7].
• We have ablated the dynamin-binding site of this protein and shown that this mutant form of amphiphysin II inhibits phagocytosis at the stage of membrane extension around the bound particles [8].
• The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56(lck), actin polymerization, and dynamin [9].
• We report here that dynamin 2, a ubiquitously expressed dynamin isoform, has a role in phagocytosis in macrophages [10].
• The dynamin family of GTPases mediates the scission of endocytic vesicles from the plasma membrane [10].

Biological context of Dnm1

• Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover [11].
• Synapse establishment is linked to an upregulation of dynamin 1 and thereby represents the beginning of the regulated recycling of membranes back into the presynaptic terminal [12].
• In this study, we examined the role of dynamin (a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC) [13].
• Inhibition of dynamin prevents migration of cells with a focal adhesion phenotype [14].
• To elucidate the molecular mechanism by which the expression is tissue-specifically regulated, we cloned the 5'-flanking region of the mouse dynamin I gene and determined the nucleotide sequence of 1036 bases upstream from the translation start site [15].

Anatomical context of Dnm1

• Overexpression of dynamin increased osteoclast bone resorbing activity and migration, whereas overexpression of dynK44A decreased osteoclast resorption and migration [11].
• Although expression of mutant dynamin in macrophages inhibited particle internalization, it had no effect on the production of inflammatory mediators elicited by particle binding [10].
• Therefore, the goal of this study was to test whether dynamin associates with caveolae via a direct binding to the caveolin 1 (Cav1) protein [16].
• We showed that overexpression of Fzo1A/B (rat) proteins involved in mitochondrial fusion, or silencing of Dnm1 (rat)/Drp1 (human) (a mitochondrial fission protein), increased elongated mitochondria in healthy cells [17].
• Therefore, dynamin may provide the trigger and actin may provide the force for movement into the cytosol [18].

Associations of Dnm1 with chemical compounds

• Endophilin B1, like endophilins A, binds to palmitoyl-CoA, exhibits lysophosphatidic acid acyl transferase activity, and interacts with dynamin, amphiphysins 1 and 2, and huntingtin [19].
• Furthermore, phosphotyrosine-containing proteins in the dynamin immunocomplexes were observed to be reactive with anticaveolin-1 antibodies [20].
• The binding of dynamin to SH3 domain-containing proteins may therefore be important for formation of the protein complex required for the endocytic processing of activated tyrosine kinase receptors [21].
• CTB entry in the Cav1-/- MEFs was predominantly clathrin and dynamin independent but relatively cholesterol dependent [22].
• Deletion from amphiphysin of its central proline-rich stretch dramatically potentiated its effect on dynamin, possibly by relieving an inhibitory intramolecular interaction [23].

Physical interactions of Dnm1

• Mouse profilin 2 regulates endocytosis and competes with SH3 ligand binding to dynamin 1 [24].
• Dynamin and the synapsins coprecipitated with Src from PC12 cell extracts, and they colocalized with a subset of Src in the PC12 cell by immunofluorescence [25].
• Mutational analysis and electrophoretic mobility-shift assay analysis revealed that Sp1 binds to the Sp1 site and that this element is critical for the promoter activity of the dynamin I gene [15].
• The platelet-derived growth factor treatment induced lamellipodia and cell migration, and dynamin II interacted with myosin II [26].
• Dynamin II interacts with syndecan-4, a regulator of focal adhesion and stress-fiber formation [27].

Enzymatic interactions of Dnm1

• Neither dynamin nor the synapsins were phosphorylated by Src, suggesting that the interaction of these proteins serves to direct the kinase activity of Src toward other proteins in the vesicle population [25].

Co-localisations of Dnm1

• In quiescent cells, dynamin II is evenly distributed in the cytoplasm and colocalizes with syndecan-4 near the nucleus [27].

Regulatory relationships of Dnm1

• The dynamin II expression level was higher when co-expressed with myosin II in Ras transformed NIH3T3 cells than in normal NIH3T3 cells [26].
• In contrast, expression of K44A/dynamin partially inhibited insulin-stimulated Shc tyrosine phosphorylation and activation of the mitogen-activated protein kinases ERK1 and -2 [2].
• In conclusion, these results suggest that dynamin II may be largely expressed and closely associated with Grb2-mediated signaling in Ras transformed cells [28].
• Furthermore, dynamin inhibited the activity of both purified recombinant and immunoprecipitated PI 3-kinase [29].
• Pretreatment with the PKC inhibitor bisindolylmaleimide II (Bis II), with sucrose (0.4 m), or through the expression of a dominant-negative form of dynamin prevents PMA-induced GLT-1 internalization and cluster formation [30].

Other interactions of Dnm1

• Thus, dynamin 2 may be the constitutive counterpart of dynamin 1 in growing neurons [12].
• The large GTPase dynamin has been shown to mediate the scission of caveolae from the plasma membrane, although it is unclear if dynamin interacts directly with caveolin or via accessory proteins [16].
• Grb2, a 24 kDa adaptor protein and an essential element of the Ras signaling pathway, was found to be associated with dynamin II and myosin II gene expression in the Ras transformed NIH3T3 cells [26].
• In immunoprecipitates containing Src and dynamin, the clathrin adaptor protein alpha-adaptin was also found [25].
• Consistent with this, immunofluorescence analysis of endophilin B1b transfected into fibroblasts shows an intracellular reticular staining, which in part overlaps with that of endogenous dynamin [19].

Analytical, diagnostic and therapeutic context of Dnm1

• Differential appearance of dynamin in constitutive and regulated exo-endocytosis: a single-cell multiplex RT-PCR study [12].
• Both dynamin and syntaxin could be detected by immunoblotting in the spinal cord at embryonic day 10 (E10; 2 days before axon outgrowth) and at all subsequent ages examined [31].
• Reverse transcription and polymerase chain reaction (RT-PCR) identified low levels of all three carboxy-terminal splicing forms of dynamin I in spinal cord from as early as E10 [31].
• Therefore, reciprocal immunoprecipitation was carried out to identify the potential relationship between dynamin II and myosin II [26].
• Assignment of the dynamin-1 gene (DNM1) to human chromosome 9q34 by fluorescence in situ hybridization and somatic cell hybrid analysis [32].

References