PPP1R8 Human
Description
Gene and Protein Structure
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Isoforms: Three splice variants are produced:
Key Domains
| Domain | Function |
|---|---|
| RVxF motif | PP1-binding domain |
| RNA-binding domain | Binds A+U-rich RNA regions |
| Nuclear localization signal | Targets protein to nucleus |
2.1. PP1 Regulation
PPP1R8 inhibits PP1 activity in the nucleus, modulating processes such as:
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Cell cycle progression: Controls phosphorylation states of cyclin-dependent kinases .
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Chromatin dynamics: Interacts with histone deacetylases (HDAC2) and PRC2 components (EZH2, EED) .
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RNA splicing: Associates with spliceosome components (e.g., SF3B1) .
2.2. RNA Metabolism
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Binds single-stranded RNA but lacks intrinsic cleavage activity in two isoforms .
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Isoform 3 exhibits RNase E-like endoribonuclease activity, critical for RNA turnover in A+U-rich regions .
2.3. Cancer Implications
PPP1R8 mutations and dysregulation are linked to carcinogenesis:
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Somatic mutations: Detected in 2% of colorectal and gastric cancers .
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Expression patterns: Ubiquitously expressed in cancer cell lines (e.g., lung, ovarian) .
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Immune modulation: In Ppp1r8 knockout mice, epidermal deletion triggers chemokine overexpression (e.g., CCL2, CXCL10), recruiting dendritic cells and causing chronic inflammation .
Interacting Proteins
PPP1R8 forms complexes with:
| Protein | Interaction Role | Source |
|---|---|---|
| PPP1CA/PPP1CB | PP1 catalytic subunits | |
| HDAC2 | Chromatin remodeling | |
| SF3B1 | Pre-mRNA splicing | |
| EZH2/EED | PRC2-mediated gene silencing |
4.1. Recombinant PPP1R8
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Production: Expressed in E. coli as a His-tagged protein (ENZ-648) .
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Applications: Used to study RNA-binding kinetics and phosphatase inhibition .
4.2. Mouse Models
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Skin-specific knockout (Ppp1r8⁻/⁻): Exhibits:
Clinical and Therapeutic Insights
Product Specs
For purification purposes, PPP1R8 is tagged with an 8 amino acid His-tag at the C-terminus and purified using proprietary chromatographic techniques.
To maintain product integrity, avoid repeated cycles of freezing and thawing.
Product Science Overview
PPP1R8 is an inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA. Instead, it may target PP-1 to RNA-associated substrates . PPP1R8 is also involved in pre-mRNA splicing, binds DNA, and might act as a transcriptional repressor . It seems to be required for cell proliferation .
The PPP1R8 gene, through alternative splicing, encodes three different isoforms . Two of these isoforms are specific inhibitors of type 1 serine/threonine protein phosphatases and can bind but not cleave RNA . The third isoform lacks the phosphatase inhibitory function but is a single-strand endoribonuclease comparable to RNase E of E. coli . This isoform requires magnesium for its function and cleaves specific sites in A+U-rich regions of RNA .
PPP1R8 is involved in several critical cellular processes, including:
- RNA Binding: It binds RNA but does not cleave it, suggesting a role in RNA metabolism .
- Pre-mRNA Splicing: It may be involved in the splicing of pre-mRNA .
- Transcriptional Repression: By binding to DNA, PPP1R8 might act as a transcriptional repressor .
- Cell Proliferation: It appears to be required for cell proliferation, indicating its importance in cell growth and division .
Mutations or dysregulation of PPP1R8 have been associated with various diseases. For instance, it is linked to Seckel Syndrome 5, a disorder characterized by growth retardation and microcephaly . Understanding the function and regulation of PPP1R8 can provide insights into the mechanisms underlying these conditions and potentially lead to therapeutic interventions.
