Disease relevance of DNM2

• The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function [1].
• These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease [2].
• X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene [3].
• Ionizing radiation-induced adenovirus infection is mediated by Dynamin 2 [4].

High impact information on DNM2

• In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion [1].
• Mutations in dynamin 2 cause dominant centronuclear myopathy [1].
• We refined the locus associated with DI-CMTB on chromosome 19p12-13.2 to 4.2 Mb in three unrelated families with CMT originating from Australia, Belgium and North America. After screening candidate genes, we identified unique mutations in dynamin 2 (DNM2) in all families [5].
• Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease [5].
• Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse [6].

Chemical compound and disease context of DNM2

• This induction (24.4- and 6.5-fold, respectively) and viral uptake were significantly diminished by preincubation with antibody for Dynamin 2 but not for Coxsackie adenovirus receptor or for integrin alpha(v) [4].

Biological context of DNM2

• RNA interference experiments confirmed that SNX9 functions as a mediator of Dyn2 recruitment to membranes in cells [7].
• A truncated dyn2 lacking the COOH-terminal proline/arginine-rich domain (PRD), which interacts with many SH3 domain-containing partners implicated in both endocytosis and signal transduction, triggers apoptosis even more potently than the wild-type [8].
• Dyn2-triggered apoptosis occurs only in dividing cells and is p53 dependent [8].
• Here, we present new evidence that the ubiquitously expressed isoform dynamin-2 (dyn2) can also function in a signal transduction pathway(s) [8].
• A </=5-fold increase of dyn2 relative to endogenous levels activates the transcription factor p53 and induces apoptosis, as demonstrated by reduced cell proliferation, DNA fragmentation, and caspase-3 activation [8].

Anatomical context of DNM2

• We show here that the complex can be activated for membrane binding of SNX9 and Dyn2 by incubation of cytosol in the presence of ATP [7].
• In this study, we demonstrate that Dyn2 and cortactin function to mediate dynamic remodeling of the actin cytoskeleton in response to stimulation with the motogenic growth factor platelet-derived growth factor [9].
• We have shown that dynamin-2 interacts with the IL-5 receptor-associated tyrosine kinases, Lyn and JAK2, in eosinophils [10].
• Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell [2].
• In GDAP1 and DNM2 mutants, both Schwann cells and axons/neurons might be directly affected [11].

Associations of DNM2 with chemical compounds

• Dynamin was inhibited by using two approaches: 1) expression of dominant negative GTPase-impaired or proline-rich domain-deleted Dyn2 mutants; and 2) inhibition of the dynamin regulator calcineurin by cyclosporin A [12].
• Dynamin-2 associates with the dopamine receptor signalplex and regulates internalization of activated D2 receptors [13].
• Using a cleavable biotin assay to quantify receptor internalization, we found that expression of dynamin-2 mutants defective in GTPase function virtually abolished agonist-induced D2R internalization [13].
• Although they differ in their ability to inhibit rapid endocytosis in adrenal chromaffin cells, the dynamin-1 and dynamin-2 PH domains showed identical phosphoinositide binding specificities [14].
• Nitric oxide promotes endothelial cell survival signaling through S-nitrosylation and activation of dynamin-2 [15].

Physical interactions of DNM2

• Furthermore, we also observed that dynamin-2 coimmunoprecipitates with KDR and is required for EC signaling/survival [16].
• In the cytosol, SNX9 is present in a 14.5 S complex containing dynamin-2 and an unidentified 41-kDa protein [17].

Co-localisations of DNM2

• In HeLa cells, SNX9 co-localized with both AP-2 and dynamin-2 at the plasma membrane or on vesicular structures derived from it but not with the early endosomal marker EEA1 or with AP-1 [17].

Regulatory relationships of DNM2

• The results suggest that SNX9-dependent recruitment of Dyn2 to the membrane is regulated by an interaction between SNX9 and aldolase [7].
• However, expression of dominant-negative dynamin-2 constructs inhibited uptake of clustered ICAM-1 [18].

Other interactions of DNM2

• Regulated membrane recruitment of dynamin-2 mediated by sorting nexin 9 [7].
• Regulatory role of dynamin-2 in VEGFR-2/KDR-mediated endothelial signaling [16].
• During caveolar trafficking, NOSTRIN functions as an adaptor to recruit mediators such as dynamin-2 essential for membrane fission [19].
• Furthermore, specific inhibition of dynamin-2 GTPase function by overexpression of a dominant negative construct, K44A, prevented the BK-mediated enrichment of eNOS-GFP within low buoyant density, caveolin-enriched fractions of eNOS-GFP ECV304 cell lysates [20].
• Unlike the internalization of detergent-resistant membrane (DRM)-associated interleukin 2 receptor, endocytosis of DRM-associated GPI-APs is unaffected by inhibition of RhoA or dynamin 2 activity [21].

Analytical, diagnostic and therapeutic context of DNM2

• Interestingly, the interaction between cortactin and dynamin 2 in cells was dependent on actin polymerization and was attenuated upon cell exposure to cytochalasin D as analyzed by immunofluorescence and immunoprecipitation [22].
• Titration of the effects showed that GTP and GDP bound to a single class of non-interacting sites in dynamin tetramers with apparent dissociation constants (K(d)) values of 5.4 and 7.4 microM (dynamin-1) and 13.2 and 7.1 microM (dynamin-2) respectively [23].
• Furthermore, gel overlay and immunoprecipitation indicated a direct interaction between gamma-tubulin and a 219-amino-acid middle domain of Dyn2 [24].
• Moreover, viral uptake in LoVo tumor xenografts was significantly increased in s.c. tumors (10.9-fold) when adenovirus was given i.v. at 24 hours after tumor irradiation, coincident with an elevated Dynamin 2 expression in irradiated tumors [4].

References