Dynamic regulation of RAS and RAS signaling

Walter Kolch1,2, Dénes Berta3, Edina Rosta3

  • 1Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.

The Biochemical Journal
|January 6, 2023
PubMed

Insights

RAS proteins are key regulators of cell function, acting as sophisticated information processors involved in cancer and developmental disorders. Their dynamic regulation controls cell fate by integrating signals, impacting diverse biological processes.

Area of Science:

  • Molecular Biology
  • Cellular Physiology
  • Biochemistry

Background:

  • RAS proteins are crucial regulators of cellular physiology, implicated in 30% of human cancers and 4% of Rasopathies.
  • They cycle between active (GTP-bound) and inactive (GDP-bound) states, interacting with effectors to control biological processes.

Purpose of the Study:

  • To explore the dynamic regulation of RAS activation and downstream signaling.
  • To understand RAS proteins as information processing devices that compute cell fate decisions.

Main Methods:

  • Review of structural and biochemical properties of RAS proteins.
  • Examination of higher molecular assemblies and effector interactions.
  • Analysis of computational and mathematical modeling approaches.

Main Results:

  • RAS proteins function as sophisticated information processing devices, not simple on/off switches.
  • Dynamic regulation of RAS activation and signaling produces a nuanced spectrum of biological outputs.
  • Computational modeling aids in understanding RAS functions in health and disease.

Conclusions:

  • The dynamic regulation of RAS signaling is critical for its complex cellular functions.
  • Understanding RAS dynamics offers insights into cancer and developmental disorders.
  • Integrated approaches, including modeling, are essential for deciphering RAS pleiotropic functions.

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.4K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
4.1K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.4K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.6K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K