PADI2

Official Full Name

peptidyl arginine deiminase 2

Organism

Homo sapiens

GeneID

11240

Background

This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type II enzyme is the most widely expressed family member. Known substrates for this enzyme include myelin basic protein in the central nervous system and vimentin in skeletal muscle and macrophages. This enzyme is thought to play a role in the onset and progression of neurodegenerative human disorders, including Alzheimer disease and multiple sclerosis, and it has also been implicated in glaucoma pathogenesis. This gene exists in a cluster with four other paralogous genes. [provided by RefSeq, Jul 2008]

Synonyms

PAD2; PDI2; PAD-H19;

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Detailed Information

Modulation of transcription in cancer induced by PADI-2 mediated arginine citrullination

At the field of post-translational modifications, non-coded amino acid citrulline led by the protein arginine deamination is a key question since its discovery by Rogers and Simmonds in 1958. A family of enzymes known as peptidyl arginine deiminases (PADIs) was responsible for the catalyzation of citrullination. In autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer, increased citrullination was associated. Understanding how citrullination works on disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation were focused during the last decade. But due to the knowledge limitations of the functional implications of citrullination, there is still a fuzziness of its role in physiological and pathological conditions. PADI-2 mediated citrullination functions in the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells, these proposed mechanisms in recent discoveries related to reshaping of the transcription regulatory network that promotes cancer progression.

ERK1/2 activation and SOX2 mRNA stability promotion in endometrial cancer induced by PADI-2 catalyzed MEK1 citrullination

The activity of PADI2 induced conversion (peptidylarginie deiminase II) from positively charged arginine residues to neutrally charged citrulline has an association with the onset and progression of multiple cancers. Based on the previous exploration of role for PADI2 in endometrial cancer (EC), mechanistically, MEK1 on extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation, which activates insulin-like growth factor-II binding protein (ICF2BP1) expression, is facilitated by PADI2 interacting and catalyzing MEK1 citrullination at arginine 113/189. Binding of IGF2BP1 to the m6A sites in SOX2-3'UTR for SOX2 mRNA degradation prevention was revealed by RNA immunoprecipitation (RIP) and RNA stability analysis. Abnormally expressing of oncogenic SOX2, which is resulted from dysregulation of IGF2BP1 in PADI2/MEK1/ERK signaling, can support the malignant state of EC. PADI2 gene silencing and MEK1 citrullination inhibition by PADI2 inhibitor equal with mutation of MEK1 R113/189 in the EC progression inhibition. Therefore, targeting PADI2/MEK1 can be a potential therapeutic approach in patients with EC.

PADI2 Figure 1. Transcription modulation in cancer by the peptidyl arginine deiminase 2 (PADI2) mediated Arginine citrullination. (Miguel Beato, et al. 2020)

References:

Beato M, Sharma P. Peptidyl arginine deiminase 2 (PADI2)-mediated arginine citrullination modulates transcription in cancer. International journal of molecular sciences, 2020, 21(4): 1351.
Xue T, Liu X, Zhang M, et al. PADI2‐Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer. Advanced Science, 2021, 8(6): 2002831.

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