# DENND2C

DENN/MADD domain containing 2C (DENND2C) is a protein that in humans is encoded by the DENND2C gene.

## Gene

DENND2C is located on human chromosome 1 at 1p13.2 on the minus strand. The gene spans about 87,200 nucleotides. and has 21 exons.
* It is a member of the DENN (Differentially Expressed in Normal and Neoplastic cells) domain-containing protein family. These proteins regulate the activity of Rab GTPases and act as Rab-specific guanine nucleotide exchange factors (GEFs).
* DENND2C also plays a crucial role in the self-renewal of human embryonic stem cells.

## mRNA

The main DENND2C mRNA isoform is 6177 nucleotides long. There are three isoforms.

## Protein

Protein isoform 1, the longest variant, is 928 amino acids long with a predicted weight of 106.9 kDa. It is alanine-poor relative to other proteins. The theoretical isoelectric point is 8.8. The protein is found in the nucleoplasm.

## Structure

The three-dimensional structure of DENND2C contains a central beta sheet flanked by alpha-helices. Details about its quaternary structure are currently unavailable.

## Clinical significance

DENND2C’s importance in cancer is highlighted by its regulation by the tumor suppressor p53. As a guanine nucleotide exchange factor for Rab (G-protein), DENND2C plays a key role in intracellular trafficking and cellular signaling. p53 helps maintain cellular balance and prevent cancer by regulating various pathways. Since DENND2C is part of the p53-regulated network, it is predicted to be involved in cancer suppression.
Disruptions in DENND2C's function or its interaction with p53 can interfere with these pathways and contribute to tumor progression. DENND2C’s role in p53-regulated pathways can be used for developing targeted cancer therapies and identifying new biomarkers for cancer diagnosis and prognosis.

## Evolutional history
### Orthologs

DENND2C has orthologs in most vertebrates: mammals, birds, reptiles, amphibians, and fish. This broad conservation highlights its significant role in vertebrates.
| | Genus/Species | Common Name | Taxonomic Group | Med. Date of Divergence (MYA) | Accession Number | Sequence Length (aa) | Sequence Identity (%) |
| Mammalia | Homo sapiens | Human | Primates | 0 | NP_001243333.1 | 928 | 100 |
| | Mus musculus | House mouse | Rodentia | 87 | XP_006501667.1 | 920 | 83.1 |
| | Orcinus orca | Killer whale | Artiodactyla | 94 | XP_049566111.1 | 935 | 89.6 |
| | Phascolarctos cinereus | Koala | Diprotodontia | 160 | XP_020857927.1 | 938 | 81.2 |
| Reptilia | Chelonia mydas | Green sea turtle | Testudines | 319 | XP_027677849.2 | 938 | 72.5 |
| | Podarcis muralis | Common wall lizard | Squamata | 319 | XP_028590394.1 | 927 | 69.9 |
| | Python bivittatus | Burmese python | Squamata | 319 | XP_007429931.1 | 928 | 69.4 |
| | Alligator mississippiensis | American alligator | Crocodilia | 319 | XP_059573447.1 | 946 | 67.9 |
| Aves | Aptenodytes forsteri | Emperor penguin | Sphenisciformes | 319 | XP_009270985.1 | 932 | 67.5 |
| | Gallus gallus | Chicken | Galliformes | 319 | XP_046788775.1 | 988 | 66.7 |
| | Tyto alba | Common barn owl | Strigiformes | 319 | XP_032843159.2 | 1018 | 65.8 |
| | Chroicocephalus ridibundus | Black-headed gull | Charadriiformes | 319 | XP_063212431.1 | 987 | 65.7 |
| Amphibia | Microcaecilia unicolor | Microcaecilia unicolor | Gymnophiona | 352 | XP_030076672.1 | 941 | 65.4 |
| | Hyla sarda | Sardinian tree frog | Anura | 352 | XP_056414351.1 | 944 | 63.1 |
| Actinistia | Latimeria chalumnae | West Indian Ocean coelacanth | Coelacanthiformes | 415 | XP_064425280.1 | 959 | 58 |
| Actinopterygii | Erpetoichthys calabaricus | Reedfish | Polypteriformes | 429 | XP_028652273.2 | 908 | 50.4 |
| | Lepisosteus oculatus | Spotted gar | Lepisosteiformes | 429 | XP_015197870.1 | 904 | 49.9 |
| | Amphiprion ocellaris | Clown anemonefish | Perciformes | 429 | XP_023154128.2 | 936 | 47.3 |
| | Phycodurus eques | Leafy seadragon | Syngnathiformes | 429 | XP_061527912.1 | 912 | 45.9 |
| | Amblyraja radiata | Thorny skate | Rajiformes | 462 | XP_032898655.1 | 1045 | 53 |
DENND2C has no known orthologs in invertebrates, bacteria, archaea, protists, plants, fungi and trichoplax. DENND2C probably evolved in more advanced multicellular organisms and is important for their specific biological functions - instead of simpler life forms like the organisms listed above.

### Parlaogs

DENND2A, DENND2B, and DENND2D are closely related paralogs of DENND2C.
| Protein | Accession Number | Sequence Identity (%) | Sequence Similarity (%) |
| DENND2C | NP_001243333.1 | 100 | 100 |
| DENND2A | NP_056504.3 | 43.4 | 57.7 |
| DENND2B | NP_001363424.1 | 38.1 | 50.6 |
| DENND2D | NP_079177.2 | 22.9 | 32.6 |

### Rate of Evolution

The protein DENND2C evolves at half the rate of fibrinogen alpha and slightly faster than cytochrome C, indicating that DENND2C has a moderately slow rate of evolution.
Cytochrome c stays similar over time (highly conserved), but fibrinogen alpha changes a lot (less conserved). The graph supports the idea that genetic changes happen steadily over time (linear), as predicted by the molecular clock hypothesis.