Tyr42 phosphorylation of RhoA GTPase promotes tumorigenesis through nuclear factor (NF)-κB

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Reactive oxygen species (ROS) dysregulation is linked to cancer pathogenesis.
• The precise molecular mechanisms of ROS in tumorigenesis remain unclear.

Purpose of the Study:

• To elucidate the role of hydrogen peroxide-induced RhoA GTPase activation in tumorigenesis.
• To investigate the molecular pathway involving RhoA phosphorylation and NF-κB activation.

Main Methods:

• Investigated hydrogen peroxide effects on RhoA GTPase and NF-κB signaling.
• Utilized tyrosine kinase Src, Vav2 GEF, and IκB kinase (IKK) complex components.
• Employed wild-type, phospho-mimic (Y42E), and dephospho-mimic (Y42F) RhoA mutants.
• Analyzed c-Myc and cyclin D1 expression and cell proliferation.
• Examined protein levels in human breast cancer tissues.

Main Results:

• Hydrogen peroxide induced RhoA phosphorylation at Tyr42 via Src kinase.
• Phospho-Tyr42 RhoA binds Vav2 GEF, leading to RhoA activation and subsequent IKKβ activation.
• RhoA WT and Y42E mutants promoted tumorigenesis and NF-κB activation, c-Myc and cyclin D1 expression, and cell proliferation.
• RhoA Y42F mutant suppressed these effects.
• Elevated p-Tyr42 RhoA, p-Src, and p-65 levels correlate in human breast cancer tissues.

Conclusions:

• Post-translational modification of RhoA at Tyr42 is crucial for ROS-induced tumorigenesis.
• The identified pathway involving ROS, RhoA phosphorylation, and NF-κB activation is a key mechanism in cancer development.