p90 ribosomal S6 kinase (RSK) phosphorylates myosin phosphatase and thereby controls edge dynamics during cell...

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Cell migration is crucial for development, healing, and cancer metastasis.
• The molecular pathways linking extracellular signals to cytoskeletal dynamics controlling cell motility are not fully understood.
• Extracellular signal-regulated kinase (ERK) is known to promote cell protrusion and motility.

Purpose of the Study:

• To elucidate the molecular mechanisms by which ERK influences cell migration, specifically its role in contractile forces.
• To investigate the downstream signaling pathways of ERK in regulating the actomyosin cytoskeleton.
• To understand how ERK coordinates protrusive and contractile forces for optimal cell motility.

Main Methods:

• Immunoblotting and co-immunoprecipitation to analyze protein interactions and phosphorylation.
• Myosin-binding experiments to assess the effects on the contractile machinery.
• Cell migration assays to quantify motility changes.
• Investigation across multiple mammalian cell lines.

Main Results:

• ERK signals through its substrate, p90 ribosomal S6 kinase (RSK), to regulate contractile forces.
• RSK phosphorylates myosin phosphatase-targeting subunit 1 (MYPT1) at Ser-507, inhibiting myosin phosphatase activity.
• This inhibition enhances the interaction between Rho kinase (ROCK) and MYPT1, promoting myosin II-mediated tension.
• ERK and RSK activity promote lamella expansion and optimal edge dynamics for cell migration.

Conclusions:

• ERK signaling coordinates both actin polymerization-driven protrusion and myosin II-mediated contraction for efficient cell migration.
• The ERK-RSK-MYPT1 pathway is a key regulator of the actomyosin cytoskeleton's contractile function in cell motility.
• These findings provide new insights into the molecular control of cell migration, relevant to development, wound healing, and cancer.