PARK2

Official Full Name

parkin RBR E3 ubiquitin protein ligase

Organism

Homo sapiens

GeneID

5071

Background

The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

Synonyms

PRKN; PDJ; AR-JP; LPRS2; PARK2;

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Detailed Information

The role of PARK2 in cancer

PARK2 has some involvement in multiple signaling pathways and cellular processes as an E3 ubiquitin ligase. A RING-between-RING-type E3 ubiquitin ligase was encoded by the PARK2 gene, which is also known as PARKIN, to serve as a RING/HECT hybrid for implicating its functions in protein turnover, stress response, mitochondria homeostasis, xenophagy, metabolism, and many other cellular processes in responsible for cell growth and survival regulations. More than this, PARK2 status also has associations with risk of autosomal recessive juvenile Parkinson's disease (ARJPD), leprosy, typhoid, and paratyphoid fever. Mice with PARK2 deficiency is susceptible to tumorigenesis, PARK2 depletion makes pancreatic cancer cells more tended to proliferate and form tumors, whereas reduced growth of cancer cells of various tissue origin can be seen in ectopic PARK2. All this may suggest a tumor suppressive role of PARK2.

PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway

As one of the most common primary malignant bone tumors, osteosarcoma (OS) has a high occurrence in children and adolescents. In recent decades, PARK2 was revealed as a vital tumor suppressor gene in many malignant solid tumors. Down-regulation of PARK2 in OS tissue and cell lines has a significant association with higher tumor stage, whereas the cell cycle is arrested by overexpression of PARK2 to inhibit cell proliferation, migration, and invasion, and reduce tube formation in vitro and tumor growth and angiogenesis in vivo. A recent finding also demonstrated that the negative association between the OS growth and PARK2 gene is partially attributed to the JAK2/STAT3/VEGF signaling pathway, which is also previously been identified as a signaling regulates several important pathways in tumorigenesis, like cell cycle progression, apoptosis, tumor invasion, and metastasis. Thus, this gene may function as a therapeutic target in various human solid tumors. And the downstream protein of the JAK2/STAT3 signaling pathway, VEGF, a usually upregulated protein in multiple cancers, plays a pivotal role in angiogenesis, and its expression is in parallel with JAK2 and STAT3 expression. Inhibition on the JAK2/STAT3/VEGF signaling exerted by the PARK2 was mainly through association with other genes and protein-protein interactions. As a recent conducted study has indicated that PARK2 depletion promotes PTEN inactivation, which was found in many human cancer cell lines with the rank as the most mutated tumor suppressor gene after p53.

Figure 1. The function of parkin and PARK2-related mutations. (Shibo Ying, et al. 2021)

References:

Madsen D A, Schmidt S I, Blaabjerg M, et al. Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson's Disease. Cells, 2021, 10(2): 283.
Xu L, Lin D, Yin D, et al. An emerging role of PARK2 in cancer. Journal of molecular medicine, 2014, 92(1): 31-42.
Lei Z, Duan H, Zhao T, et al. PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway. Cell Death & Disease, 2018, 9(3): 1-13.

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