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Related Concept Videos

Rab Proteins01:14

Rab Proteins

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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
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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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MAPK Signaling Cascades01:07

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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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Amplifying Signals via Enzymatic Cascade01:22

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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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Receptor Tyrosine Kinases01:26

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Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
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Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42,...
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Related Experiment Video

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Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
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Phosphorylation-driven effector switching of Rab7 and Rab12 by the leucine-rich repeat kinase 1 in mast cells.

Jana Omar-Kabha1, Sewar Omari1, Yaara Gorzalczany1

  • 1Department of Cellular, Developmental, and Regenerative Biology, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.

Frontiers in Immunology
|December 8, 2025
PubMed
Summary

Mast cell activation triggers phosphorylation of Rab GTPases Rab7 and Rab12 via LRRK1, influencing their interactions with RILP proteins and regulating mediator release.

Keywords:
IgELRRK1LRRK2MRGPRX2Rab12Rab7mast cellsprotein kinase C

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Area of Science:

  • Immunology
  • Cell Biology
  • Neuroinflammation

Background:

  • Mast cells (MCs) are key players in immune, allergic, and neuroinflammatory responses.
  • Rab12 regulates mediator release from MCs by interacting with the RILP-dynein complex.
  • The role of phosphorylation in modulating Rab12 interactions with its effectors, including RILP-like proteins, was previously unknown.

Purpose of the Study:

  • To investigate whether phosphorylation controls Rab12 distribution among its RILP family effectors (RILP, RILP-L1, RILP-L2).
  • To identify the kinases involved in the phosphorylation of Rab12 and Rab7 upon mast cell activation.

Main Methods:

  • Pulldown assays were employed to assess the interactions between Rab12 and its effectors.
  • Mast cell activation was induced using IgE/antigen or substance P.
  • Inhibition studies using protein kinase C (PKC) and leucine-rich repeat kinase 2 (LRRK2) inhibitors were performed.
  • Knockdown of Leucine-Rich Repeat kinase 1 (LRRK1) was utilized to determine its role in phosphorylation.

Main Results:

  • Mast cell activation via IgE/antigen or substance P induced phosphorylation of Rab7 and Rab12.
  • Phosphorylation was sensitive to PKC inhibition but resistant to LRRK2 inhibition, implicating LRRK1.
  • LRRK1 knockdown suppressed Rab7 and Rab12 phosphorylation, indicating LRRK1 acts via a PKC-dependent mechanism.
  • LRRK1-mediated phosphorylation of Rab12 enhanced its binding to RILP-L1/L2 and reduced binding to RILP.
  • LRRK1 phosphorylation of Rab7 enhanced its affinity for RILP.

Conclusions:

  • LRRK1, through a PKC-dependent pathway, phosphorylates Rab7 and Rab12 upon mast cell activation.
  • This phosphorylation event alters the binding preferences of Rab12 and Rab7 to their RILP family proteins.
  • These findings reveal a novel regulatory mechanism controlling mast cell mediator release.