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Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
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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...
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Interactions Between Signaling Pathways01:19

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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
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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...
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Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
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Identifying the Binding Proteins of Small Ligands with the Differential Radial Capillary Action of Ligand Assay DRaCALA
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Identifying the Binding Proteins of Small Ligands with the Differential Radial Capillary Action of Ligand Assay DRaCALA

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A signalling cascade for Ral.

You Wu, David J Reiner1

  • 1Texas A&M University, Houston, TX, USA.

Small Gtpases
|May 6, 2021
PubMed
Summary
This summary is machine-generated.

Ras signaling through RalGEF>Ral is poorly understood. Invertebrate studies reveal a Ras>RalGEF>Ral>GCK-2>p38 MAP kinase cascade, clarifying Ras effector pathway functions in vivo.

Keywords:
Exo84Exoc-8ExocystLET-60MLK-1PMK-1Ral-1Rgl-1Sec-5Sec5hppymsn

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Area of Science:

  • Cellular signaling pathways
  • Oncogenic signaling
  • MAP kinase cascades

Background:

  • Ras is a key oncoprotein in cancer, with RalGEF>Ral signaling being the least understood effector pathway.
  • Previous research in Drosophila identified Ral's role in apoptosis and its links to MAP4 Kinase misshapen and JNK MAP kinase basket.
  • Key signaling components differ between model organisms, necessitating studies in organisms like C. elegans.

Approach:

  • Utilized C. elegans vulval precursor cell (VPC) development for analyzing Ras signaling pathways.
  • Investigated the functions of paralogous CNH-domain MAP4 Kinases MIG-15 and GCK-2 in relation to Ras>Raf, Notch, and Ras>RalGEF>Ral signaling.
  • Employed CRISPR and genetic epistasis to delineate the Ras>RalGEF>Ral signaling cascade.

Key Points:

  • MIG-15 (nematode misshapen ortholog) antagonizes both Ral-dependent and Ras>Raf-dependent outcomes in VPC development.
  • GCK-2 (C. elegans happyhour ortholog) propagates Ral's pro-developmental signal.
  • A Ras>RalGEF>Ral>Exo84>GCK-2>MAP3K^MLK-1>p38^PMK-1 cascade was defined.

Conclusions:

  • Genetic analysis in invertebrate models elucidated a novel signaling cascade from Ras to p38 MAP kinase via the RalGEF>Ral pathway.
  • This research provides crucial insights into the in vivo function of Ral signaling, a critical but understudied Ras effector.