Distinct functions of dynamin isoforms in tumorigenesis and their potential as therapeutic targets in cancer - PubMed (original) (raw)

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Distinct functions of dynamin isoforms in tumorigenesis and their potential as therapeutic targets in cancer

Jianghui Meng. Oncotarget. 2017.

Abstract

Dynamins and their related proteins participate in the regulation of neurotransmission, antigen presentation, receptor internalization, growth factor signalling, nutrient uptake, and pathogen infection. Recently, emerging findings have shown dynamin proteins can also contribute to the genesis of cancer. This up-to-date review herein focuses on the functionality of dynamin in cancer development. Dynamin 1 and 2 both enhance cancer cell proliferation, tumor invasion and metastasis, whereas dynamin 3 has tumor suppression role. Antisense RNAs encoded on the DNA strand opposite a dynamin gene regulate the function of dynamin, and manipulate oncogenes and tumor suppressor genes. Certain dynamin-related proteins are also upregulated in distinct cancer conditions, resulting in apoptotic resistance, cell migration and poor prognosis. Altogether, dynamins are potential biomarkers as well as representing promising novel therapeutic targets for cancer treatment. This study also summarizes the current available dynamin-targeted therapeutics and suggests the potential strategy based on signalling pathways involved, providing important information to aid the future development of novel cancer therapeutics by targeting these dynamin family members.

Keywords: amphiphysin; cancer target; clathrin; endocytosis; tumor.

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Conflict of interest statement

CONFLICTS OF INTEREST

The author declares that there is no conflict of interest.

Figures

Figure 1

Figure 1. Schematic diagram for resting and stimulated receptor-mediated endocytosis in neurons and differential involvement of dynamin isoforms in stimulated receptor-mediated endocytosis

Using a molecular probe, such as botulinum neurotoxin (BoNT) which cleaves SNARE proteins, to dissect the path of receptor-mediated endocytosis [115], it was revealed that resting uptake by neurons occurs via lipid rafts, acidified compartments and protein acceptors but not dynamin. In contrast, stimulated endocytosis of BoNT by neurons utilises lipid rafts, acidified compartments (Vacuolar-type H+ -ATPase) and dynamin and amphiphysin [4]. In terms of fast recycling of small clear synaptic vesicles, cerebellar granule neurons (CGNs) use predominantly dynamin 1, whereas isoform 2 and, to a lesser extent, isoform 3 to support a less rapid mode of stimulated endocytosis. In contrast, large dense-cored vesicle (LDCV)-releasing trigeminal ganglionic neurons (TGNs) preferentially employ dynamins 2 and 3 and amphiphysin 1 for evoked endocytosis. PM = plasma membrane, V-H+ = Vacuolar-type H+, CCP = clathrin coated pit, CME = clathrin mediated endocytosis.

Figure 2

Figure 2. Distinct localization of dynamin isoforms in the peripheral neurons highlights their distinct functional importance

The linear domain arrangement of human dynamin and related proteins. A. Immuno-fluorescence study demonstrated that dynamin 1 and 2 showed distinct distribution pattern in the cultured trigeminal ganglionic neuron. Dynamin 1, green; dynamin 2, red; nuclei, blue. B. Each domain of dynamin protein is indicated as follows: G domain, yellow, is responsible for GTP binding and hydrolysis; middle coiled-coil domain– GTPase Effector Domain (GED) stalk, blue, is responsible for dynamin protein self-assembly, and variant splicing; PH domain (pleckstrin homology), green, is responsible for lipid binding; GED, orange, is responsible for ring assembling and also enhance GTPase activity; PRD (proline rich domain), light purple, interacts with SH3-domain partners, such as amphyphisin; N-terminal MIS (mitochondrial import sequence): dark purple, is responsible for targeting the OPA1 protein; B insert domain (pink) of the Dnm1 guanosine triphosphatase (a Drp) contains a novel motif required for association with the mitochondrial adaptor Mdv1 to the mitochondria.

Figure 3

Figure 3. Schematic map for potential targets in dynamin-mediated tumor development whereas dynamin 1 and 2 act as the tumor promotors

In contrast, dynamin 3 has tumor suppressive role. Inhibition or depletion of the Akt/GSK3β signalling pathway will prevent the function of dynamin 1 in lung cancer cells. Moreover, inhibition of dynamin 2 interaction with Vav1 will stop the activation of Rac1, and a method that prevents phosphorylation of PDGFRα-PI3K/SHP-2 will reduce the increased tumor growth and cancer cell invasion in certain types of cancer. Blockage of hypermethylation of DNM3 by some genetic approach or increase of expression of dynamin 3 protein will prevent the tumor development.

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