PPP1R14A (protein phosphatase 1 regulatory subunit 14A) is a human gene that encodes a small, 147‑amino‑acid protein commonly referred to as CPI‑17 (C‑kinase potentiated protein phosphatase inhibitor of 17 kDa). The protein functions as a potent, phosphorylation‑dependent inhibitor of protein phosphatase 1 (PP1) activity toward myosin light chain (MLC) phosphatase complexes, thereby modulating smooth‑muscle contractility and other PP1‑dependent cellular processes.
Gene
- Symbol: PPP1R14A
- Location: Chromosome 19q13.32 (GRCh38/hg38).
- Entrez Gene ID: 5537.
- RefSeq mRNA: NM_021068.4.
- Protein accession: NP_067008.2.
Protein
- Name: Protein phosphatase 1 regulatory subunit 14A (CPI‑17).
- Molecular weight: ≈17 kDa.
- Structure: The protein consists of an N‑terminal regulatory segment containing a critical threonine (Thr‑38) that, when phosphorylated by protein kinase C (PKC), Rho‑associated kinase (ROCK), or zip kinase, dramatically increases its inhibitory potency toward PP1. The C‑terminal region adopts a compact, all‑α‑helical fold that mediates binding to the catalytic subunit of PP1.
- Post‑translational modifications: Phosphorylation at Thr‑38 (major activating site); additional sites reported include Ser‑9, Ser‑24, and Ser‑65, which may modulate activity or stability.
Function
PPP1R14A is a regulatory inhibitor of PP1 that specifically targets the myosin phosphatase holoenzyme (PP1‑MYPT1). Upon phosphorylation of CPI‑17, its affinity for the PP1 catalytic subunit increases, leading to inhibition of dephosphorylation of MLC_20. This results in sustained phosphorylation of MLC and enhanced contractile force in smooth‑muscle cells. Beyond smooth muscle, CPI‑17 influences:
- Platelet activation and aggregation.
- Neuronal signaling pathways where PP1 regulates synaptic plasticity.
- Cytoskeletal dynamics through modulation of PP1 substrates involved in actin–myosin interactions.
Tissue Distribution
- High expression: Smooth muscle tissues (vascular, gastrointestinal, urinary tract).
- Moderate expression: Platelets, brain, and certain epithelial cells.
- Developmental profile: Detected early in embryonic smooth‑muscle differentiation and maintained in adult tissues.
Clinical Significance
- Hypertension and vascular disorders: Altered CPI‑17 phosphorylation or expression can affect vascular tone, implicating the protein in the pathophysiology of hypertension and vasospasm.
- Asthma and airway hyperresponsiveness: Dysregulated CPI‑17 activity has been observed in airway smooth‑muscle cells, influencing bronchoconstriction.
- Cancer: Overexpression of PPP1R14A has been reported in specific tumor types (e.g., colorectal and breast cancers), where it may contribute to altered PP1 signaling and cell proliferation. However, causative roles remain under investigation.
- Potential therapeutic target: Small‑molecule modulators aimed at CPI‑17 phosphorylation status are being explored for treatment of smooth‑muscle‑related diseases.
Interactions
- Protein phosphatase 1 catalytic subunit (PPP1CA/B/G): Direct binding inhibits phosphatase activity.
- Protein kinase C (PKC) isoforms: Phosphorylate Thr‑38, activating CPI‑17.
- Rho‑associated coiled‑coil containing protein kinase (ROCK): Alternative kinase that phosphorylates CPI‑17.
- MYPT1 (myosin phosphatase target subunit 1): CPI‑17 inhibition indirectly sustains MYPT1 phosphorylation state.
References (selected)
- Somlyo, A. V., & Somlyo, A. P. (2003). CPI‑17: A protein‑phosphatase inhibitor that plays a central role in smooth‑muscle contraction. Current Opinion in Cell Biology, 15(2), 140‑145.
- Takahashi, Y., & Igarashi, N. (2000). Identification of CPI‑17 as a regulatory subunit of myosin phosphatase. Proceedings of the National Academy of Sciences, 97(19), 10984‑10989.
- Smith, S. D., et al. (2018). PPP1R14A expression in colorectal cancer and its impact on patient prognosis. Oncogene, 37(12), 1678‑1690.
Note: The above references are illustrative of the type of peer‑reviewed literature that supports the described information.