YAP controls cell migration and invasion through a Rho GTPase switch

Area of Science:

• Cell Biology
• Molecular Oncology
• Cancer Research

Background:

• Cell movement is fundamental to physiological and pathological processes.
• The transcriptional coactivator YAP plays roles in development and is linked to cancer metastasis.
• Rho family GTPases (Rac1, RhoA) are critical regulators of cytoskeletal dynamics and cell motility.

Purpose of the Study:

• To elucidate the mechanisms by which YAP controls cell migration.
• To investigate the role of YAP in modulating Rho GTPase signaling.
• To explore the therapeutic potential of targeting the YAP pathway in cancer, especially glioblastoma.

Main Methods:

• Investigated YAP's transcriptional regulation of TRIO via intronic enhancer binding.
• Assessed the impact of YAP-TRIO signaling on Rac1 and RhoA activation.
• Evaluated cell migration and invasion in vitro and in vivo.
• Analyzed gene expression signatures (YAP, TRIO, STAT3) in patient glioblastoma samples.

Main Results:

• YAP directly transactivated TRIO, a Rac1 guanine nucleotide exchange factor.
• YAP-induced TRIO activation led to Rac1 activation and RhoA inhibition, enhancing cell migration and invasion.
• This YAP-dependent pathway was observed in various cell types and was particularly pronounced in glioblastoma.
• YAP-TRIO signaling activated STAT3, suggesting pathway cross-talk that may promote invasive growth.

Conclusions:

• The YAP-TRIO-Rho-GTPase signaling network is a key regulator of invasive cell spread.
• Hyperactivation of YAP, TRIO, and STAT3 is associated with poor patient survival in glioblastoma.
• Targeting this pathway may offer therapeutic strategies for invasive cancers.