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PubMed2006

C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells.

Dynamins are large GTPases that act in multiple vesicular trafficking events. We identified 14 loss-of-function alleles of the C. elegans dynamin gene, dyn-1, that are defective in the removal of apoptotic cells. dyn-1 functions in engulfing cells to control the internalization and degradation of apoptotic cells. dyn-1 acts in the genetic pathway composed of ced-7 (ABC transporter), ced-1 (phagocytic receptor), and ced-6 (CED-1's adaptor). DYN-1 transiently accumulates to the surface of pseudopods in a manner dependent on ced-1, ced-6, and ced-7, but not on ced-5, ced-10, or ced-12. Abnormal vesicle structures accumulate in engulfing cells upon dyn-1 inactivation. dyn-1 and ced-1 mutations block the recruitment of intracellular vesicles to pseudopods and phagosomes. We propose that DYN-1 mediates the signaling of the CED-1 pathway by organizing an intracellular vesicle pool and promoting vesicle delivery to phagocytic cups and phagosomes to support pseudopod extension and apoptotic cell degradation.

Alleles↗
PubMed2002

Antagonist-induced micro-opioid receptor up-regulation decreases G-protein receptor kinase-2 and dynamin-2 abundance in mouse spinal cord.

Chronic treatment with opioid receptor antagonists has been shown to increase the density of micro-, delta- and kappa-opioid receptors in cell culture and in the intact animal. Although opioid receptor antagonist-induced up-regulation is a robust phenomenon, the mechanisms responsible for the increase in receptor density remain unclear. In the present study, changes in a kinase and a GTPase that have been implicated in G-protein-coupled receptor regulation were examined following opioid receptor antagonist treatment. Mice were implanted s.c. with a naltrexone pellet or placebo pellet. On the eighth day following implantation, spinal cord was removed and G-protein receptor kinase-2 (GRK-2) and dynamin-2 abundance were determined using a quantitative immunoblot approach. Changes in micro-opioid receptor density were also determined. Naltrexone treatment produced a significant (145%) increase in micro-opioid receptor density. Naltrexone treatment was associated with a significant 36% decrease in GRK-2 and 30% decrease in dynamin-2 abundance in spinal cord. These data raise the possibility that opioid receptor antagonist-induced micro-opioid receptor up-regulation in the intact animal may be due to a reduction in constitutive internalization of opioid receptors.

Animals↗
PubMed2005

Assay and functional analysis of dynamin-like protein 1 in peroxisome division.

Recent studies have demonstrated that peroxisome division requires at least one dynamin-like protein, Vps1p, in the yeast Saccharomyces cerevisiae and DLP1 (DRP1) in mammalian cells. Although the requirement for these proteins in peroxisome division is supported by many lines of evidence, their roles in peroxisome division have yet to be identified. Given the independence of peroxisomes from other organelle systems, the peroxisome system appears to have unique attributes for studying the function of dynamin-like proteins in organelle division. Here, we present methods that have been used for studying the role of DLP1 in peroxisome biogenesis and division.

Animals↗
PubMed2005

Assay and functional analysis of dynamin-like Mx proteins.

Mx proteins are interferon-induced large guanosine triphosphatases (GTPases) that share structural and functional properties with dynamin and dynamin-like proteins, such as self-assembly and association with intracellular membranes. A unique property of some Mx proteins is their antiviral activity against a range of RNA viruses, including influenza viruses and members of the bunyavirus family. These viruses are inhibited at an early stage in their life cycle, soon after host cell entry and before genome amplification. The association of the human MxA GTPase with membranes of the endoplasmic reticulum seems to support its antiviral function by providing an interaction platform that facilitates viral target recognition, MxA oligomerization, and missorting of the resulting multiprotein complex into large intracellular aggregates.

3T3 Cells↗
PubMed2000

The dynamin family of mechanoenzymes: pinching in new places.

The large GTPase dynamin is a mechanoenzyme that mediates the liberation of nascent clathrin-coated pits from the plasma membrane during endocytosis. Recently, this enzyme has been demonstrated to comprise an extensive family of related proteins that have been implicated in a large variety of vesicle trafficking events during endocytosis, secretion and even maintenance of mitochondrial form. The potential contributions by the dynamin family to these diverse but related functions are discussed.

Actins↗
PubMed2004

Life-long effects of perinatal asphyxia on stress-induced proteins and dynamin 1 in rat brain.

In previous work, we have shown that perinatal asphyxia (PA) in the rat leads to life-long neurotransmitter deficits and impairment of cognitive functions and behavior. This observation made us examine protein expression in hippocampus of rats with PA at the end of the life span. We applied a well-documented and characterized animal model of PA. Pups, normoxic and asphyxiated for 20 min, were brought up until the age of 24 months and then were sacrificed. Hippocampal tissue was dissected from the brains, and proteins were run on two-dimensional gel electrophoresis with in-gel digestion and subsequent identification of proteins by MALDI-TOF followed by quantification of protein spots by specific software. In hippocampus of rats with PA, the stress proteins protein disulfide isomerase A3 precursor and stress-induced phosphoprotein-1 were significantly increased, whereas the microtubule-associated protein dynamin-1 was significantly reduced. Increased stress protein levels may represent long-term effects of PA or, alternatively, could reflect conditioning of the stress protein machinery known to occur as a neuroprotective principle following hypoxic-ischemic conditions. Decreased dynamin-1 levels may be considered as a long-term effect on the exocytotic system possibly reflecting or leading to impaired neuronal transport and vesicle-trafficking in PA of the rat of advanced age.

Aging↗
PubMed2002

Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits.

As a final step in endocytosis, clathrin-coated pits must separate from the plasma membrane and move into the cytosol as a coated vesicle. Because these events involve minute movements that conventional light microscopy cannot resolve, they have not been observed directly and their dynamics remain unexplored. Here, we used evanescent field (EF) microscopy to observe single clathrin-coated pits or vesicles as they draw inwards from the plasma membrane and finally lose their coats. This inward movement occurred immediately after a brief burst of dynamin recruitment and was accompanied by transient actin assembly. Therefore, dynamin may provide the trigger and actin may provide the force for movement into the cytosol.

3T3 Cells↗
PubMed1994

Crystal structure of the pleckstrin homology domain from dynamin.

The pleckstrin homology (PH) domain is a conserved module present in many signal transducing and cytoskeletal proteins. Here we report the 2.8 A crystal structure of the PH domain from dynamin. This domain consists of seven beta-strands forming two roughly orthogonal antiparallel beta-sheets terminating with an amphipathic alpha-helix. The structure also reveals a non-covalent dimeric association of the PH domain and a hydrophobic pocket surrounded by a charged rim. The dynamin PH domain structure is discussed in relation to its potential role in mediating interactions between proteins.

Amino Acid Sequence↗
PubMed2003

The dynamin-like protein ADL1C is essential for plasma membrane maintenance during pollen maturation.

Dynamin-related GTPases regulate a wide variety of dynamic membrane processes in eukaryotes. Here, we investigated the function of ADL1C, a member of the Arabidopsis 68 kDa dynamin-like protein family. Analysis of heterozygous adl1C-1 indicates that the mutation specifically affects post-meiotic male gametogenesis. Fifty percent of the mature pollen from heterozygous adl1C-1 androecia are shriveled and fail to germinate in vitro. During microspore maturation, adl1C-1 pollen grains display defects in the plasma membrane and intine morphology, suggesting that ADL1C is essential for the formation and maintenance of the pollen cell surface and viability during desiccation. Consistent with a role in cell-surface dynamics, immunofluorescence microscopy indicates that ADL1C is localized to the cell plate of dividing somatic cells and to the tip of expanding root hairs. We propose that ADL1C functions in plasma membrane dynamics, and we discuss the role of the ADL1 family in plant growth and development.

Antibodies↗
PubMed2002

Imaging direct, dynamin-dependent recapture of fusing secretory granules on plasma membrane lawns from PC12 cells.

During exocytosis, secretory granules fuse with the plasma membrane and discharge their content into the extracellular space. The exocytosed membrane is then reinternalized in a coordinated fashion. A role of clathrin-coated vesicles in this process is well established, whereas the involvement of a direct retrieval mechanism (often called kiss and run) is still debated. Here we report that a significant population of docked secretory granules in the neuroendocrine cell line PC12 fuses with the plasma membrane, takes up fluid-phase markers, and is retrieved at the same position. Fusion allows for complete discharge of small molecules, whereas GFP-labeled neuropeptide Y (molecular mass approximately equal 35 kDa) is only partially released. Retrieved granules were preferentially associated with dynamin. Furthermore, recapture is inhibited by guanosine 5'-[gamma-thio]triphosphate and peptides known to block dynamin function. We conclude that secretory granules can be recaptured immediately after formation of an exocytotic opening by an endocytic reaction that is spatially and temporally coupled to soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent fusion, but is not a reversal of the fusion reaction.

Animals↗
PubMed2001

Regulation of membrane-type matrix metalloproteinase 1 activity by dynamin-mediated endocytosis.

Membrane-type matrix metalloproteinase 1 (MT1-MMP) plays a critical role in extracellular matrix remodeling under both physiological and pathological conditions. However, the mechanisms controlling its activity on the cell surface remain poorly understood. In this study, we demonstrate that MT1-MMP is regulated by endocytosis. First, we determined that Con A induces proMMP-2 activation in HT1080 cells by shifting endogenous MT1-MMP from intracellular compartments to cell surface. This phenotype was mimicked by the cytoplasmic truncation mutant MT1 Delta C with more robust pro-MMP-2 activation and cell surface expression than wild-type MT1-MMP in transfected cells. MT1 Delta C was subsequently shown to be resistant to Con A treatment whereas MT1-MMP remains competent, suggesting that Con A regulates MT1-MMP activity through cytoplasmic domain-dependent trafficking. Indeed, MT1-MMP was colocalized with clathrin on the plasma membrane and with endosomal antigen 1 in endosomes. Internalization experiments revealed that MT1-MMP is internalized rapidly in clathrin-coated vesicles whereas MT1 Delta C remains on cell surface. Coexpression of a dominant negative mutant of dynamin, K44A, resulted in elevation of MT1-MMP activity by interfering with the endocytic process. Thus, MT1-MMP is regulated by dynamin-dependent endocytosis in clathrin-coated pits through its cytoplasmic domain.

Animals↗
PubMed1995

Stimulation of human monocytes with macrophage colony-stimulating factor induces a Grb2-mediated association of the focal adhesion kinase pp125FAK and dynamin.

Macrophage colony-stimulating factor (M-CSF) is required for the growth and differentiation of mononuclear phagocytes. In the present studies using human monocytes, we show that M-CSF induces interaction of the Grb2 adaptor protein with the focal adhesion kinase pp125FAK. The results demonstrate that tyrosine-phosphorylated pp125FAK directly interacts with the SH2 domain of Grb2. The findings indicate that a pYENV site at Tyr-925 in pp125FAK is responsible for this interaction. We also demonstrate that the Grb2-FAK complex associates with the GTPase dynamin. Dynamin interacts with the SH3 domains of Grb2 and exhibits M-CSF-dependent tyrosine phosphorylation in association with pp125FAK. These findings suggest that M-CSF-induced signaling involves independent Grb2-mediated pathways, one leading to Ras activation and another involving pp125FAK and a GTPase implicated in receptor internalization.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Rapid endocytosis coupled to exocytosis in adrenal chromaffin cells involves Ca2+, GTP, and dynamin but not clathrin.

Rapid endocytosis (RE) occurs immediately after an exocytotic burst in adrenal chromaffin cells. Capacitance measurements of endoocytosis reveal that recovery of membrane is a biphasic process that is complete within 20 sec. The ultimate extent of membrane retrieval is precisely controlled and capacitance invariably returns to its prestimulation value. The mechanism of RE specifically requires intracellular Ca2+; Sr2+ and Ba2+ do not substitute, although all three cations support secretion. Thus the divalent cation receptors for RE and exocytosis must be distinct molecules. RE is dependent on GTP hydrolysis; it is blocked by GTP removal or replacement with guanosine 5'-[gamma-thio]triphosphate. In the presence of GTP, multiple rounds of secretion followed by RE could be elicited from the same cell. RE requires participation of dynamin, a guanine nucleotide binding protein, as revealed by intracellular immunological antagonism of this protein. Intact microtubules may be essential, as nocodazole also blocked RE. Whereas anti-dynamin antibodies blocked RE, anti-clathrin antibodies did not, suggesting that clathrin-coated vesicles are not involved in this form of endocytosis. RE may represent the initial step in the rapid recycling of secretory granules in the chromaffin cell.

Adrenal Glands↗
PubMed1999

Dynamin-dependent endocytosis of ionotropic glutamate receptors.

Little is known about the mechanisms that regulate the number of ionotropic glutamate receptors present at excitatory synapses. Herein, we show that GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) are removed from the postsynaptic plasma membrane of cultured hippocampal neurons by rapid, ligand-induced endocytosis. Although endocytosis of AMPARs can be induced by high concentrations of AMPA without concomitant activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs), NMDAR activation is required for detectable endocytosis induced by synaptically released glutamate. Activated AMPARs colocalize with AP2, a marker of endocytic coated pits, and endocytosis of AMPARs is blocked by biochemical inhibition of clathrin-coated pit function or overexpression of a dominant-negative mutant form of dynamin. These results establish that ionotropic receptors are regulated by dynamin-dependent endocytosis and suggest an important role of endocytic membrane trafficking in the postsynaptic modulation of neurotransmission.

Adaptor Protein Complex 2↗
PubMed1997

Decreased endosomal delivery of major histocompatibility complex class II-invariant chain complexes in dynamin-deficient cells.

Major histocompatibility complex class II molecules are heterodimeric cell surface molecules which acquire antigenic peptides in the endosomal/lysosomal system. Invariant chain (Ii), a third chain which is associated with class II molecules intracellularly mediates the endosomal targeting, but it is debated whether class II molecules reach the endosomal system mainly from the trans-Golgi network or via the cell surface. Dynamin is a cytosolic GTPase which is necessary for the formation of clathrin-coated vesicles from the plasma membrane, but which is not required for vesicle formation from the trans-Golgi network. Here we have used HeLa cells expressing a dominant negative form of dynamin to show that inhibition of clathrin-mediated uptake from the plasma membrane leads to accumulation of transfected Ii-class II complexes at the cell surface, while delivery of such complexes to endosomes/lysosomes is decreased. Our data therefore suggest that in this experimental system the majority of Ii-class II complexes traverse the cell surface before they reach the endosomal system.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2000

Acute regulation of Na+/H+ exchanger NHE3 by parathyroid hormone via NHE3 phosphorylation and dynamin-dependent endocytosis.

Parathyroid hormone (PTH) is a potent inhibitor of mammalian renal proximal tubule Na(+) transport via its action on the apical membrane Na(+)/H(+) exchanger NHE3. In the opossum kidney cell line, inhibition of NHE3 activity was detected from 5 to 45 min after PTH addition. Increase in NHE3 phosphorylation on multiple serines was evident after 5 min of PTH, but decrease in surface NHE3 antigen was not detectable until after 30 min of PTH. The decrease in surface NHE3 antigen was due to increased NHE3 endocytosis. When endocytic trafficking was arrested with a dominant negative dynamin mutant (K44A), the early inhibition (5 min) of NHE3 activity by PTH was not affected, whereas the late inhibition (30 min) and decreased surface NHE3 antigen induced by PTH were abrogated. We conclude that PTH acutely inhibits NHE3 activity in a biphasic fashion by NHE3 phosphorylation followed by dynamin-dependent endocytosis.

Animals↗
PubMed2000

Role of dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone.

G-protein-coupled receptors are a large group of integral membranal receptors, which in response to ligand binding initiate diverse downstream signaling. Here we studied the gonadotropin-releasing hormone (GnRH) receptor, which uses Gq for its downstream signaling. We show that extracellular signal-regulated kinase (ERK) activation is fully dependent on protein kinase C (PKC), but only partially dependent on Src, dynamin, and Ras. Receptor tyrosine kinases, FAK, Gbetagamma, and beta-arrestin, which were implicated in some G-protein-coupled receptor signaling to MAPK cascades, do not play a role in the GnRH to ERK pathway. Our results suggest that the activation of ERK by GnRH involves two distinct signaling pathways, which converge at the level of Raf-1. The main pathway involves a direct activation of Raf-1 by PKC, and this step is partially dependent on a second pathway consisting of Ras activation, which occurs in a dynamin-dependent manner, downstream of Src.

Animals↗
PubMed2002

The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum.

Mx proteins are induced by type I interferon and inhibit a broad range of viruses by undefined mechanisms. They are included within the dynamin family of large GTPases, which are involved in vesicle trafficking and share common biophysical features. These properties include the propensity to self-assemble, an affinity for lipids, and the ability to tubulate membranes. In this report we establish that human MxA, despite sharing only 30% homology with conventional dynamin, possesses many of these properties. We demonstrate for the first time that MxA self-assembles into rings that tubulate lipids in vitro, and associates with a specific membrane compartment in cells, the smooth endoplasmic reticulum.

Antiviral Agents↗