NLK is required for Ras/ERK/SRF/ELK signaling to tune skeletal muscle development by phosphorylating SRF and

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Shang-Ze Li1,2, Ze-Yan Zhang1, Jie Chen1

  • 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, 430072, Wuhan, Hubei, China.

Cell Death Discovery
|January 11, 2022
PubMed

Insights

Nemo-like kinase (NLK) promotes serum response factor/ELK signaling by phosphorylating SRF, enhancing ELK binding. This pathway is crucial for muscle development, as NLK inhibition leads to muscle hypertrophy in mice.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Developmental Biology

Background:

  • Serum response factor (SRF) is a key regulator of cell differentiation and proliferation.
  • SRF activity is modulated by coactivators like MKL and ELK, but the precise regulatory mechanisms are not fully understood.
  • The Ras-MAPK pathway influences ELK activity, impacting SRF-mediated gene expression.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating SRF activity.
  • To investigate the role of Nemo-like kinase (NLK) in SRF signaling.
  • To determine the impact of NLK-mediated SRF regulation on muscle development.

Main Methods:

  • Investigated protein-protein interactions between NLK, SRF, and ELK in human and mouse cells.
  • Utilized in vitro assays to assess the effect of NLK phosphorylation on SRF-ELK association.
  • Generated and analyzed a skeletal muscle-specific Nlk conditional knockout mouse model.

Main Results:

  • NLK directly interacts with and phosphorylates SRF at serine residues 101/103.
  • NLK-mediated phosphorylation of SRF enhances its association with the ELK transcriptional coactivator.
  • This enhanced SRF/ELK interaction antagonizes the SRF/MKL pathway, inhibiting myoblast differentiation and leading to muscle hypertrophy in knockout mice.

Conclusions:

  • NLK is a critical promoter of SRF/ELK signaling through direct phosphorylation of SRF.
  • The NLK-SRF-ELK axis plays a significant role in antagonizing SRF/MKL signaling and modulating muscle differentiation.
  • NLK is essential for normal muscle development, with its absence resulting in increased muscle mass.

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