Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Protein kinase N2 connects blood flow with NO production in a double AKT
David J.R. Fulton, David W. Stepp
David J.R. Fulton, David W. Stepp
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e154256. https://doi.org/10.1172/JCI154256.
View: Text | PDF
Commentary Article has an altmetric score of 4

Protein kinase N2 connects blood flow with NO production in a double AKT

  • Text
  • PDF
Abstract

Shear stress is an important regulator of blood flow, and luminal endothelial cells (ECs) sense increases in frictional forces and respond with an appropriate release of vasoactive mediators. In this issue of the JCI, Jin et al. identified a mechanism by which ECs respond to shear stress with endothelial NOS (eNOS) activation and NO release. The authors showed that PKN2 was activated by fluid shear stress and contributed to eNOS activation via a double play — indirect phosphorylation at serine 1177 (S1177) via AKT and direct phosphorylation of the S1179 site. Phosphorylation of both sites individually increased eNOS activity, but together they had an additive effect. In sum, these findings reveal exciting details about how shear stress regulates eNOS and have important implications for blood flow and blood pressure.

Authors

David J.R. Fulton, David W. Stepp

×

Figure 1

Mechanisms that regulate shear stress signaling and eNOS in ECs.

Options: View larger image (or click on image) Download as PowerPoint
Mechanisms that regulate shear stress signaling and eNOS in ECs.
(A) Acu...
(A) Acute laminar shear stress activates the mechanosensor Piezo1, triggering the release of ATP and the activation of P2Y2, which together promote the activating phosphorylation of PDK1 in a manner dependent on calcium (Ca2+). How calcium contributes to the phosphorylation of PDK1 is not yet known. p-PDK1 then phosphorylates PNK2 at T816, resulting in the phosphorylation of AKT1 at T308, which leads to indirect phosphorylation of eNOS at S1177, an activating site (16), as well to direct phosphorylation of eNOS at S1179, a site described by Jin et al. (3) that increases eNOS activity. (B) Alignment of the C-termini of three human NOS (panel B was adapted from data in ref. 14). The calcium-dependent NOS isoforms (eNOS and nNOS) possess a C-terminal autoinhibitory domain that contains S1177 (eNOS) and an equivalent residue on nNOS, and both the autoinhibitory domain and internal phosphorylation site are absent in calcium-insensitive iNOS. S1179 is present in eNOS, but not nNOS or iNOS, suggesting a mechanism unique to eNOS. (C) S1179 lies just outside of the C-terminal autoinhibitory domain on human eNOS, which acts to facilitate calcium/CaM-dependent activation.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 6 X users
3 readers on Mendeley
See more details