Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1

Area of Science:

• Cellular Biology
• Molecular Oncology
• Signal Transduction

Background:

• Ras proteins are key transducers of growth factor signaling, activating mTORC1, which integrates nutrient and energy signals.
• Feedback loops between Ras/MAPK and mTORC1 pathways are crucial for coordinating cell division and growth.
• Oncogenic Ras isoforms (H-ras and K-ras) play distinct roles in tumor progression and stemness.

Purpose of the Study:

• To investigate a novel feedback mechanism from mTORC1 impacting oncogenic H-ras and K-ras signaling.
• To elucidate how this feedback affects the stemness properties of tumor cells.
• To understand the differential effects of mTORC1 on H-ras and K-ras signaling output.

Main Methods:

• Studied the role of SREBP1 processing and its downstream effects on lipid metabolism.
• Investigated the impact of SREBP1 modulation on the membrane organization and signaling of oncogenic H-ras and K-ras.
• Examined the effects of phosphatidic acid modulation on Ras isoform activity.
• Assessed the promotion of mammospheres as a measure of stemness.

Main Results:

• mTORC1 activation increases processed SREBP1, a lipid metabolism regulator.
• SREBP1 modulation downstream of S6K1 oppositely affects H-ras and K-ras membrane organization and signaling.
• Modulation of phosphatidic acid is sufficient to differentially impact H-ras and K-ras in the cell membrane.
• mTORC1 activation enhances H-ras signaling but decreases K-ras signaling in transformed cells.

Conclusions:

• A novel negative feedback loop from mTORC1 oppositely regulates oncogenic H-ras and K-ras signaling.
• This differential regulation impacts tumor cell stemness, with implications for cancer therapy.
• Targeting this feedback mechanism may offer strategies for inhibiting cancer stem cells.