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Oncogenic KRas mobility in the membrane and signaling response

Ruth Nussinov1, Chung-Jung Tsai2, Hyunbum Jang2

  • 1Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Seminars in Cancer Biology
|March 3, 2018
PubMed

Insights

Ras protein diffusion speed influences signaling response times, particularly for MAPK pathways, when Ras expression leads to dimerization. However, KRas mobility may not be functionally significant.

Area of Science:

  • Cellular Biology
  • Biophysics

Background:

  • Ras signaling is initiated at the plasma membrane, making Ras behavior and interactions with downstream effectors like Raf and PI3Kα critical areas of study.
  • Understanding factors influencing Ras lateral diffusion is key to elucidating its role in cellular signaling.

Purpose of the Study:

  • To investigate whether the diffusion speed of oncogenic Ras in the membrane impacts signaling response times.
  • To determine if Ras diffusion speed affects all signaling pathways ubiquitously or specific ones.

Main Methods:

  • Review of factors influencing Ras lateral diffusion.
  • Analysis of the relationship between Ras diffusion speed, dimerization/nanoclustering, and signaling response times for MAPK and PI3Kα pathways.

Main Results:

  • Ras diffusion speed correlates with signaling response times for pathways involving Ras dimers or nanoclusters, such as MAPK signaling.
  • The signaling response time for PI3Kα is not affected by Ras diffusion speed.
  • Lateral diffusion speeds of KRas, HRas, and Lck kinase are similar despite anchor variability, while Cdc42 shows a different mobility pattern.

Conclusions:

  • Ras diffusion speed is functionally relevant for pathways dependent on Ras dimerization or nanoclustering.
  • KRas diffusion speed may not play a significant functional role due to limited impact of mobility changes.
  • Protein mobility patterns, like that of Cdc42, can evolve for specific cellular functions, indicating tailored adaptations beyond general diffusion.
Keywords:
Cdc42HRASK-RasK-Ras4AK-Ras4BKRAS4AKRAS4BLck kinaseNRAS

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