Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway

Pui-Kei Wu1, Andrew Becker1, Jong-In Park1,2

  • 1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Insights

The Raf/MEK/extracellular signal-regulated kinase (ERK) pathway controls cell growth and survival. This review explores how pathway-level regulation, not just downstream effects, dictates cell fate and growth inhibition.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • The Raf/MEK/ERK pathway is a key regulator of cellular processes, including proliferation and survival.
  • This signaling cascade can also induce cell cycle arrest and death, exhibiting paradoxical outputs.
  • Emerging evidence points to pathway-level regulation influencing these diverse cellular outcomes.

Purpose of the Study:

  • To review recent advancements in understanding the molecular mechanisms of growth inhibitory signaling mediated by the Raf/MEK/ERK pathway.
  • To highlight the critical role of pathway-level regulation in determining cellular fate.
  • To focus on how magnitude, spatial-temporal dynamics, and non-canonical functions impact pathway activity.

Main Methods:

  • Literature review of recent studies on Raf/MEK/ERK pathway signaling.
  • Analysis of molecular mechanisms governing growth inhibition.
  • Synthesis of findings related to pathway-level regulatory strategies.

Main Results:

  • The Raf/MEK/ERK pathway's output (proliferation vs. growth inhibition) is influenced by pathway-level characteristics.
  • Key regulatory aspects include signal magnitude, spatial-temporal dynamics, and the function of pathway components.
  • Pathway-level control offers a nuanced understanding beyond traditional downstream effector analysis.

Conclusions:

  • Regulation at the pathway level is crucial for determining the cell fate response to extracellular stimuli.
  • Understanding these mechanisms provides insights into controlling growth inhibitory signaling.
  • This review emphasizes the importance of studying the entire pathway for a comprehensive view of its biological roles.

Related Concept Videos

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...
7.6K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.0K
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...
7.0K
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...
4.5K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
11.3K
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...
6.9K