PADI1

Official Full Name

peptidyl arginine deiminase 1

Organism

Homo sapiens

GeneID

29943

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 I enzyme is involved in the late stages of epidermal differentiation, where it deiminates filaggrin and keratin K1, which maintains hydration of the stratum corneum, and hence the cutaneous barrier function. This enzyme may also play a role in hair follicle formation. This gene exists in a cluster with four other paralogous genes. [provided by RefSeq, Jul 2008]

Synonyms

PDI; PAD1; PDI1; HPAD10;

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Detailed Information

ERK1/2-p38 signaling pathway activated by PADI1 in pancreatic ductal adenocarcinoma

Five members (PADI1-4,6) consisted the peptidyl arginine deiminase (PADI) family could post-translationally convert arginine residues into neutrally charged citrulline within a highly organized gene cluster at 1p36.13 in humans and on the orthologous region of mouse chromosome 4. The important role of PADI-mediated protein citrullination in various cancers has also been reported. In a recent report by Qin et al, tumorigenesis suppression of PADI1 in triple negative breast cancer was demonstrated to be correlated with ERK1/2 and p38 MAPK signaling pathways activation.

As one of the most leading causes of digestive tract malignancy-related death, pancreatic ductal adenocarcinoma (PAAD), which is accounted for nearly 85% of pancreatic cancer, has some poorness in its prognosis despite great progress that has been made in the traditional therapeutic treatments, such as surgery resection, chemotherapy or radiotherapy. So, the revelation of the underlying molecular mechanisms for improving the prognosis of this disease is of great importance. The effects of PADI1 on PAAD cell migration, invasion, EMT and ERK1/2-p38 signaling were analyzed by loss-of-function and gain-of-function assays. More than this, regulation of PADI1 on PAAD cell migration and invasion via regulating ERK1/2-p38 signaling pathway was further confirmed by rescue experiments.

Glycolysis and cancer cell proliferation can be regulated by the PADI1 mediated pyruvate kinase citrullination

As an ATPase subunit of the Nucleosome Remodeling and Deacetylation (NuRD) complex, chromodomain helicase DNA binding protein 4 (CHD4) has played an essential role in multiple patient derived melanoma xenografts or breast cancer progression. CHD4 regulated PADI1 (Protein Arginine Deiminase 1) expression in multiple cancer cell types for the citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2) modulation has been shown in several studies. The cross-talk between PKM2 ligands and PKM2 R106 can be reprogrammed by its citrullination, thus lowering its sensitivity to the inhibitors and promoting activation by Serine. So, the low Serine levels in charged normal physiological regulation bypassed by the citrullination can promote excessive glycolysis and reduced cell proliferation. And up-regulation of PADI1 can be seen in hypoxia where PKM2 citrullination contributes to increased glycolysis. Conversion of arginine to citrulline influenced interaction within PKM2, within which it is also in concert to its activity reprogramming, may provide a new insight for revelation of this important enzyme regulation mechanism.

Figure 1. Hypothetical model of the transcriptional regulation of human PADI1 gene by cross talk between its promoter and NF-κB mediated signaling pathway. (Shibo Ying, et al. 2010)

References:

Ji T, Ma K, Chen L, et al. PADI1 contributes to epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma through activating ERK1/2-p38 signaling pathway. Journal of Gastrointestinal Oncology,2021.
Ying S, Kojima T, Kawada A, et al. An intronic enhancer driven by NF-κB contributes to transcriptional regulation of peptidyl arginine deiminase type I gene in human keratinocytes. Journal of investigative dermatology, 2010, 130(11): 2543-2552.

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