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Unphosphorylated MARCKS is involved in neurite initiation induced by insulin-like growth factor-I in SH-SY5Y cells

Mitsuya Shiraishi1, Atsuhiro Tanabe, Naoaki Saito

  • 1Laboratory of Pharmacology, School of Pharmaceutical Science, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan. shiraishim@pharm.kitasato-u.ac.jp

Journal of Cellular Physiology
|August 31, 2006
PubMed

Insights

Myristoylated alanine-rich C kinase substrate (MARCKS) dephosphorylation promotes neurite outgrowth. Unphosphorylated MARCKS is crucial for actin cytoskeleton organization and neurite initiation in neuronal cells.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Myristoylated alanine-rich C kinase substrate (MARCKS) is implicated in neuronal differentiation and neurite outgrowth.
  • The regulatory mechanisms of MARCKS phosphorylation and its specific role in neurite outgrowth remain unclear.

Purpose of the Study:

  • To investigate the role of MARCKS phosphorylation in insulin-like growth factor-I (IGF-I)-induced neurite outgrowth.
  • To elucidate the signaling pathways regulating MARCKS phosphorylation and its impact on neuronal cell morphology.

Main Methods:

  • SH-SY5Y cells were treated with IGF-I, PI3K inhibitors (LY294002, wortmannin), and ROCK inhibitor (Y27632).
  • Changes in phosphorylated MARCKS (P-MARCKS) levels, RhoA activity, and MARCKS localization were assessed.
  • MARCKS and its mutants were overexpressed to evaluate their effect on neurite formation.

Main Results:

  • IGF-I treatment caused a rapid decrease in P-MARCKS levels, which was blocked by PI3K and ROCK inhibitors.
  • IGF-I induced RhoA inactivation and MARCKS translocation to the membrane, colocalizing with F-actin at lamellipodia and neurite tips.
  • Overexpression of MARCKS, including an unphosphorylatable mutant, enhanced neurite-bearing cell numbers.

Conclusions:

  • Unphosphorylated MARCKS plays a key role in initiating neurite outgrowth.
  • MARCKS is essential for organizing the actin cytoskeleton during IGF-I-stimulated neuronal differentiation.
  • The PI3K/RhoA/ROCK pathway regulates MARCKS phosphorylation, influencing neurite formation.

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