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The DENN (differentially expressed in normal and neoplastic cells) domain is an evolutionarily conserved module found in all eukaryotes. Members of the Rab family of small GTPases, acting as guanine nucleotide exchange factors (GEFs). The GEF activity resides in the DENN domain itself. DENND5B, also known as Rab6IP-like, shares a very similar structure with DENND5A. In addition to the typical DENN domains, DENND5B contain two RUN (RPIP8/UNC-14/NESCA) domains that have been presumed to constitute protein modules related to the function of Rabs, and which act as components of vesicle trafficking and interact with motor proteins, such as kinesin or myosin, additionally, DENND5B contain a PLAT (Polycystin-1/Lipoxygenases/Alpha-Toxin) domain, which has been found in proteins that interact with phospholipid bilayers.
DENND5B's expression levels. Differences in expression levels of any gene is fundamental to biological research. According to the experiments，DENND5B is expressed in a selection of tissues at different levels, but the brain is where it is most abundant (Fig 1)，which is similar to the expression pattern of DENND5A, DENND5A plays a critical role in the proper establishment of apical polarity during developmental stages of the nervous system, leading to massive brain malformations in patients with DENND5A point mutations, so DENND5B may be able to play a similar role in the developmental stages of the nervous system.
Fig 1. Expression patters of DENND5A and DENND5B in multiple tissues
(Source: McGill University. 2022.)
Intracellular localization. Studies have shown that different DENN domain-containing proteins have been associated with a large variety of membrane trafficking processes. In co-localization experiments using multiple Golgi markers, the results show that DENND5B localizes to the Golgi and is distributed throughout the Golgi rather than being restricted to any specific subregion. Furthermore, immunofluorescence studies and proteomic analyses suggest that DENND5B is involved in the Golgi-derived secretory pathway and that the interaction of DENND5B with the motor protein MYO5A is associated with the transport of Golgi-derived secretory vesicles through actin filaments for their further maturation and release into the extracellular space.
Unconventional Myosin-Va. Unconventional Myosin-Va (MYO5A) was the most abundant protein after DENND5B and is a promising binding candidate. MYO5A belongs to the myosin superfamily of molecular motors, which serve in vesicle transport and organelle retention at specific locations in the cell. In neurons, it has been shown that MYO5A can regulate the exocytosis of secretory vesicles by participating in the maturation, transport, and exocytosis of large dense-core vesicles (LDCVs), the neuronal equivalent of SGs. By using DENND5B as a binding protein to co-immunoprecipitate MYO5A in mouse brain, we were able to confirm the interaction between DENND5B and MYO5A.
Valosin-containing protein. The transitional Endoplasmic Reticulum ATPase, also known as valosin-containing protein (VCP), VCP is an essential AAA (ATPase associated with various cellular activities) protein that participates in multiple cellular processes, including cell cycle regulation, organelle formation, vesicular sorting, and protein homeostasis via the ubiquitin-proteasome system and the autophagosomal/lysosomal system. Since VCP has the intrinsic property to bind protein aggregates for further degradation, it is speculated that one possible explanation for this interaction is that VCP binds to misfolded proteins, and a possible explanation for this interaction is that VCP with misfolded DENND5B is a target for degradation.
DENND5B is essential for Golgi to plasma membrane transport of chylomicron secretory vesicles, consequently affecting body mass composition and changes in plasma lipids when loss-of-function mutations occur. During normal intracellular trafficking processes, enterocytes rely on the formation and secretion of chylomicrons for secretion and further absorption of dietary fat. It has been proposed that DENND5B regulates membrane fusion events between the chylomicron secretory vesicles and the plasma membrane since these events were rarely observed in duodenal sections of DENND5B knock-out mice using electron microscopy, resulting in the reduction of dietary fats like cholesterol and phospholipids after oil-gavage experiments. Additionally, DENN5B knock-out mice were resistant to western diet-induced obesity up to 50 to 70 percent by shifting their body composition to increasingly global lean mass compared to control mice
Recent studies have linked the aberrant expression of DENND5B with some of the most frequently diagnosed malignancies. A recent meta-analysis of multiple genome-wide association studies aimed to identify new risk loci variations for colorectal cancer (CRC) in the East Asians population, found an intronic risk variation in the intron 8 of DENND5B to be one of the first low-frequency variations associated with CRC. A further analysis that aimed to construct a competing endogenous RNA (ceRNA) regulation network for CRC found that patients with high expression of DENND5B mRNA had significantly poor overall survival compared to those with low expression, suggesting that DENND5B functions as a promising prognostic biomarker for CRC. Additionally, two independent studies with the aim of constructing ceRNAs networks for Wilms' tumor, one of the most common types of childhood kidney cancer, showed that high expression levels of the long non-coding RNA (lncRNA) DENND5B-AS1 was correlated with tumor stage and poor survival rate in patients with Wilms' tumor.
References
| Target | Cat. No. | Product Name | Host | Isotype | Application | |
| DENND5B | DCABH-15161 | Anti-DENND5B monoclonal antibody | Rabbit | IgG | WB, ELISA | Inquiry |
| CABT-L4504R | Rabbit Anti-Human DENND5B polyclonal antibody | Rabbit | IgG | IHC, ICC/IF | Inquiry | |
| CABT-BL4504 | Anti-DENND5B (aa 1073-1102) polyclonal antibody | Rabbit | IgG | WB | Inquiry |
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