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FLASH GENE

Symbol

DNM2

contributors: mct/shn - updated : 28-11-2018

HGNC name	dynamin 2
HGNC id	2974

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal tripartite GTPase domain
	a PH (pleckstrin homology) domain, that binds phosphoinositides with a very low affinity and this interaction appears to be crucial for its function
	a intermediary middle domain
	a basic proline rich C terminus that contains multiple SRC homology 3 (SH3) domains and nine consensus motifs for p34 Cdc2 kinase

HOMOLOGY

interspecies	ortholog to Dnm2, Mus musculus
	ortholog to Dnm2, Rattus norvegicus
	ortholog to dnm2, danio rerio
	ortholog to DNM2, Pan troglodytes

Homologene

FAMILY

dynamin family

CATEGORY

enzyme , regulatory , transport

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus
text	microtubule associated (centriolar)
	localizes predominantly at the I-band and perinuclear regions, two regions of intense membrane trafficking in muscle
	DNM2 is primarily confined to the inner segment compartment of photoreceptors

basic FUNCTION	large GTPase multidomain, potentially involved in the G2/mitosis transition and in vesicle trafficking
	having a role in endocytosis at the plasma membrane, membrane trafficking from the trans-Gogi network, formation of actin-stress fibers, actin-membrane interface assembly and centrosome cohesion
	involved in endocytosis (
	can act as a signal transducing GTPase affecting transcriptional regulation (
	regulates actin assembly and actin filament organization at membranes through an interaction with cortactin (
	implicated in actin assembly in phagocytosis in Sertoli cells
	involved in actin dynamics and the formation of dynamin 2-positive ruffles during phagocytosis
	may play a role during acrosome formation and/or acrosomal exocytosis
	with cortactin, functions as a dynamic actin filament remodeling complex that influences the global organization of the actomyosin cytoskeleton
	important function in the downregulation of growth factor receptor tyrosine kinases such as the EGFR
	involved in endocytosis and intracellular membrane trafficking
	participates in internalization and degradation of the gap junction plaque but also in recycling of Cx43 to the plasma membrane through respectively Rab5/Rab7 and Rab11 pathways (
	DNM1, DNM2, DNM3, decode action potential firing for synaptic vesicle recycling
	potential role in retina outer segment protein transport
	AMPH functions synergistically with full-length DNM2 to catalyze vesicle release
	PQBP1 and DNM2 are components of a signaling pathway that orchestrates neuronal ciliary morphogenesis in the brain
	acts within lamellipodia to organize actin filaments and regulate assembly and flow of lamellar actomyosin
	cardiac membrane-remodelling GTPase, modulates ion channels membrane trafficking in the cardiomyocytes
	DNM2-dependent endocytosis plays a major role in megakaryocyte (MK) membrane formation and thrombopoiesis
	role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis
	essential role of DNM2 GTPase in preserving normal biphasic insulin secretion and blood glucose homeostasis
	regulates insulin secretory capacity and dynamics through a mechanism depending on clathrin-mediated endocytosis (CME) and F-actin remodeling
	acts potentially as a "break" to prevent excess or potentially toxic NO levels under high-salt conditions
	dynamin family of proteins play important regulatory roles in membrane remodelling and endocytosis, especially within brain and neuronal tissues
	DNM1 and DNM2 act as key mediators of sperm acrosome formation and function
	GTPase essential for intracellular vesicle formation and trafficking, cytokinesis and receptor endocytosis

CELLULAR PROCESS	cell cycle, checkpoint

PHYSIOLOGICAL PROCESS

endocytosis transport , cellular trafficking transport

PATHWAY

metabolism

signaling

a component	forming a protein complex with FNBP1, SRGAP2 and WAS
	syndapin-dynamin complexes, crucial and sufficient to promote vesicle formation from the trans-Golgi network
	complex formation of FNBP1 with WAS, WIPF1, and dynamin-2 at the plasma membrane is critical for the formation of podosomes and phagocytic cups
	SH3KBP1–DNM2 complex appears to function predominantly at later stages of EGFR trafficking, namely in the transport of receptors from RAB7-positive late endosomes
	component of the neuromuscular junction post-synaptic compartment
	DNM2, CLTC and lipid rafts mediate SLC12A1 endocytosis and maintain steady-state apical surface SLC12A1 in native renal thick ascending limb (THAL)
	addition of NME1 or NME2 to DNM2 facilitates DNM2 oligomerization and increases GTPase activity, both required for vesicle scission

INTERACTION

DNA

RNA

small molecule

nucleotide,

protein	GTP binding protein with GTPase activity
	syndapin II isoform interacting with the proline-rich domain (PRD) of dynamin II through its Src-homology 3 (SH3) domain
	cortactin, profilin, syndapin, and murine Abp1 (
	sorting nexin 9, SNX9 (
	Rho family guanine nucleotide exchange factor Vav1 (
	amphiphysin (
	SH3KBP1
	PQBP1 interacts with DNM2 and thereby inhibits its GTPase activity
	DNM2 dependent endocytosis of FGFR1 is required for angiogenesis in response to FGF2 and the non-classical FGF ligand, FGF21
	GJB2-DNM2 interaction involves the C-terminus of GJB2 and the GTPase effector domain of DNM2, which is of particular importance for the regulation of the endocytic pathway, and DNM2 regulates GJB2 endocytosis and ubiquitination
	ARF6 functions as a downstream molecule of DNM2 in clathrin-mediated endocytosis (CME)
	novel ARF6 activation mechanism by DNM2 through PSD3 and PSD4 in CME in a manner dependent upon the GTPase activity of DNM2
	MIB1 promotes the interaction between DNM2 and SNX18 in an ubiquitin ligase activity-dependent manner
	IKZF1 directly binds the DNM2 promoter and suppresses DNM2 expression
	SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting DNM2

cell & other

REGULATION

Other

DNM2 activity may be temporally regulated by phosphorylation of DNM2 via the kinase CDK1 in spermatogonia, and dephosphorylation by phosphatase PPP3CA during meiotic and post-meiotic spermatogenesis

ASSOCIATED DISORDERS

corresponding disease(s)

DICMT1 , CNM2 , LCCS5 , SPG69

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in late-onset Alzheimer disease, results in the accumulation of APP in lipid raft-rich plasma membranes tumoral     --over   is associated with IKAROS dysregulation and may be important in the development of B- Acute Lymphoblastic Leukemia constitutional     --low   coupled with severe ventricular arrhythmias

Susceptibility

to late-onset Alzheimer disease (LOAD)

Variant & Polymorphism other	polymorphisms increasing the risk of late-onset Alzheimer disease (LOAD)

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular rythm   with its multi-ion channel targeting properties, could be a promising target for novel antiarrhythmic therapies

ANIMAL & CELL MODELS

in isolated muscle fibers from wild-type and HTZ mice, Dnm2 localized in regions of intense membrane trafficking (I-band and perinuclear region), emphasizing the pathophysiological hypothesis in which Dnm2-dependent trafficking would be altered