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Related Concept Videos

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...
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
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 the...
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
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Related Experiment Video

Updated: May 20, 2026

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
12:27

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

Published on: June 8, 2022

Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate.

Yugesh Kharel1, Mithun Raje, Ming Gao

  • 1Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.

The Biochemical Journal
|July 4, 2012
PubMed
Summary

A new selective SphK2 inhibitor increases blood sphingosine 1-phosphate (S1P) levels, unlike SphK1 inhibitors. This finding provides a biomarker for target engagement and aids in understanding S1P regulation.

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Area of Science:

  • Lipid signaling
  • Pharmacology
  • Immunology

Background:

  • Sphingosine 1-phosphate (S1P) is a key lipid mediator regulating cell survival, migration, and lymphocyte trafficking via five G-protein-coupled receptors (S1P1-S1P5).
  • Sphingosine kinases (SphKs), particularly SphK1 and SphK2, synthesize S1P. SphK2's unique nuclear localization suggests distinct functions, yet selective inhibitors are scarce.

Purpose of the Study:

  • To develop and characterize a selective SphK2 inhibitor.
  • To investigate the impact of SphK2 inhibition on circulating S1P levels.
  • To establish a biomarker for SphK2 target engagement.

Main Methods:

  • Synthesis and characterization of a novel cationic amphiphilic small molecule inhibitor selective for SphK2.
  • Administration of SphK2 and SphK1 inhibitors to wild-type mice.
  • Analysis of circulating S1P levels in wild-type, SphK1-null, and SphK2-null mice.

Main Results:

  • The novel SphK2 inhibitor selectively inhibits SphK2 activity.
  • Administration of the SphK2 inhibitor led to a rapid increase in blood S1P levels in wild-type mice.
  • SphK2-null mice exhibited higher circulating S1P levels, while SphK1-null mice showed lower levels, mirroring inhibitor effects.
  • Circulating S1P levels correlated with SphK2 inhibitor levels, indicating target engagement.

Conclusions:

  • Selective SphK2 inhibition increases circulating S1P levels, contrasting with SphK1 inhibition.
  • SphK1 and SphK2 activity differentially regulate systemic S1P levels.
  • Circulating S1P serves as a reliable biomarker for SphK2 inhibitor engagement.