SH4-domain-induced plasma membrane dynamization promotes bleb-associated cell motility

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• SH4 domains are known to target proteins to the plasma membrane.
• Oncogenic Src family kinases play roles in cell signaling and cancer progression.

Purpose of the Study:

• To investigate novel functions of SH4 domains beyond membrane targeting.
• To explore the role of SH4 domains in plasma membrane dynamics and cell behavior.

Main Methods:

• Induction of plasma membrane blebbing using SH4 domains from Src kinases and Leishmania HASPB.
• Analysis of blebbing kinetics and dependence on Rho GTPase signaling pathways.
• Investigation of the roles of Rock kinase, myosin II, F-actin, and microtubules in SH4-induced blebbing.
• Assessment of Src kinase activity and enrichment in blebs.
• Correlation of blebbing with cell invasion in 3D matrices.

Main Results:

• SH4 domains induce dynamic, non-apoptotic plasma membrane blebbing.
• Blebbing is regulated by Rho GTPase signaling, Rock kinase, myosin II, F-actin, and microtubules.
• Endogenous Src kinase activity is essential for SH4-induced blebbing.
• Active Src and Rock kinases accumulate in blebs.
• SH4-induced blebbing correlates with increased cell invasion.

Conclusions:

• SH4 domains possess a novel conserved activity of inducing plasma membrane dynamization.
• SH4-domain-mediated blebbing links Src activity and Rho signaling to cell invasiveness.
• This mechanism is relevant for understanding the role of SH4-domain-containing oncoproteins in cancer progression.