Target type: biologicalprocess
Any process that stops, prevents, or reduces the frequency, rate or extent of receptor mediated endocytosis, the uptake of external materials by cells, utilizing receptors to ensure specificity of transport. [GOC:go_curators]
Negative regulation of receptor-mediated endocytosis is a complex process that involves a variety of cellular mechanisms aimed at reducing the internalization of specific molecules into the cell. These mechanisms are essential for maintaining cellular homeostasis and responding to external stimuli.
Here's a detailed breakdown of the process:
**1. Signal Recognition and Receptor Binding:**
- The process begins with a specific ligand, such as a hormone, growth factor, or nutrient, binding to its corresponding receptor protein on the cell surface. This interaction triggers a signaling cascade, leading to the activation of intracellular pathways.
**2. Receptor Internalization:**
- Upon ligand binding, the receptor-ligand complex undergoes a conformational change, leading to the recruitment of adaptor proteins and clathrin. Clathrin molecules assemble into a lattice-like structure, forming a clathrin-coated pit around the receptor-ligand complex.
- The pit then invaginates and eventually pinches off from the plasma membrane, forming a clathrin-coated vesicle containing the internalized receptor-ligand complex.
**3. Endosomal Trafficking:**
- The clathrin-coated vesicle detaches from the plasma membrane and fuses with an early endosome. Inside the endosome, the receptor-ligand complex undergoes sorting.
- Some receptors are recycled back to the plasma membrane, while others are targeted for degradation.
**4. Receptor Degradation:**
- In some cases, the receptor-ligand complex is transported to late endosomes and then to lysosomes, where it undergoes degradation.
- Lysosomes are acidic organelles containing hydrolytic enzymes that break down the receptor-ligand complex into its constituent parts.
**5. Negative Regulation:**
- Negative regulation of receptor-mediated endocytosis can occur at multiple steps in the process:
- **Ligand Binding Inhibition:** Blocking the binding of the ligand to its receptor can prevent the initiation of the endocytosis pathway.
- **Receptor Downregulation:** Reducing the number of receptors on the cell surface can limit the amount of ligand that can bind and be internalized.
- **Endosomal Sorting Modulation:** Altering the sorting mechanisms within endosomes can lead to the degradation of receptors rather than their recycling, effectively decreasing receptor availability.
- **Clathrin Assembly Inhibition:** Preventing the formation of clathrin-coated pits can block the internalization of receptors.
**6. Importance of Negative Regulation:**
- Negative regulation of receptor-mediated endocytosis plays crucial roles in:
- **Fine-tuning cellular responses:** By controlling the amount of ligand internalized, cells can precisely regulate the activation of specific intracellular signaling pathways.
- **Preventing overstimulation:** Negative regulation prevents the accumulation of receptors or excessive signaling, which can be detrimental to cellular function.
- **Cellular adaptation and homeostasis:** By modulating receptor levels and signaling pathways, cells can adapt to changing environmental conditions and maintain a steady state.
**7. Examples of Negative Regulation:**
- **Ligand-induced receptor degradation:** In some cases, the binding of a ligand to its receptor triggers the internalization and degradation of the receptor, effectively reducing the cell's responsiveness to further ligand stimulation.
- **Protein Kinase C (PKC) activation:** PKC activation can phosphorylate and downregulate certain receptors, leading to their internalization and degradation.
- **Ubiquitination:** The attachment of ubiquitin molecules to receptors can target them for degradation.
Overall, negative regulation of receptor-mediated endocytosis is a complex and tightly regulated process that ensures the proper functioning of cells in response to a variety of stimuli.'
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Protein | Definition | Taxonomy |
---|---|---|
Ras-related C3 botulinum toxin substrate 1 | A Ras-related C3 botulinum toxin substrate 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P63000] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
fasudil | fasudil : An isoquinoline substituted by a (1,4-diazepan-1-yl)sulfonyl group at position 5. It is a Rho-kinase inhibitor and its hydrochloride hydrate form is approved for the treatment of cerebral vasospasm and cerebral ischemia. fasudil: intracellular calcium antagonist; structure in first source | isoquinolines; N-sulfonyldiazepane | antihypertensive agent; calcium channel blocker; EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor; geroprotector; neuroprotective agent; nootropic agent; vasodilator agent |
ketorolac | 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid : A member of the class of pyrrolizines that is 2,3-dihydro-1H-pyrrolizine which is substituted at positions 1 and 5 by carboxy and benzoyl groups, respectively. ketorolac : A racemate comprising equimolar amounts of (R)-(+)- and (S)-(-)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. While only the (S)-(-) enantiomer is a COX1 and COX2 inhibitor, the (R)-(+) enantiomer exhibits potent analgesic activity. A non-steroidal anti-inflammatory drug, ketorolac is mainly used (generally as the tromethamine salt) for its potent analgesic properties in the short-term management of post-operative pain, and in eye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis. It was withdrawn from the market in many countries in 1993 following association with haemorrhage and renal failure. Ketorolac: A pyrrolizine carboxylic acid derivative structurally related to INDOMETHACIN. It is an NSAID and is used principally for its analgesic activity. (From Martindale The Extra Pharmacopoeia, 31st ed) | amino acid; aromatic ketone; monocarboxylic acid; pyrrolizines; racemate | analgesic; cyclooxygenase 1 inhibitor; cyclooxygenase 2 inhibitor; non-steroidal anti-inflammatory drug |
sanguinarine chloride | |||
chelerythrine chloride | |||
perifosine | ammonium betaine; phospholipid | EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor | |
ruboxistaurin | ruboxistaurin: inhibits protein kinase C beta; structure in first source | ||
s 1033 | (trifluoromethyl)benzenes; imidazoles; pyridines; pyrimidines; secondary amino compound; secondary carboxamide | anticoronaviral agent; antineoplastic agent; tyrosine kinase inhibitor | |
sotrastaurin | sotrastaurin : A member of the class of maleimides that is maleimide which is substituted at position 3 by an indol-3-yl group and at position 4 by a quinazolin-4-yl group, which in turn is substituted at position 2 by a 4-methylpiperazin-1-yl group. It is a potent and selective inhibitor of protein kinase C and has been investigated as an immunosuppresant in renal transplant patients. sotrastaurin: a potent protein kinase C-selective inhibitor; structure in first source | indoles; maleimides; N-alkylpiperazine; N-arylpiperazine; quinazolines | anticoronaviral agent; EC 2.7.11.13 (protein kinase C) inhibitor; immunosuppressive agent |
gdc-0973 | cobimetinib : A member of the class of N-acylazetidines obtained by selective formal condensation of the carboxy group of 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid with the secondary amino group from the azetidine ring of 3-[(2S)-piperidin-2-yl]azetidin-3-ol. An inhibitor of mitogen-activated protein kinase that is used (as its fumarate salt) in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma. cobimetinib: has antineoplastic activity; structure in first source | aromatic amine; difluorobenzene; N-acylazetidine; organoiodine compound; piperidines; secondary amino compound; tertiary alcohol | antineoplastic agent; EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor |
azd5438 | sulfonamide | ||
nsc 23766 | NSC 23766 trihydrochloride : A hydrochloride resulting from the formal reaction of NSC 23766 with 3 mol eq. of hydrogen chloride. An inhibitor of the signalling G-protein known as RAC1 (Ras-related C3 botulinum toxin substrate 1). Rac1 inhibitor : Any inhibitor of Rac1. | hydrochloride | antiviral agent; apoptosis inducer; EC 3.6.5.2 (small monomeric GTPase) inhibitor; muscarinic antagonist |
at13148 | |||
poziotinib | HM781-36B: antitumor irreversible Pan-HER inhibitor for treatment of gastric cancer | acrylamides; aromatic ether; dichlorobenzene; diether; monofluorobenzenes; N-acylpiperidine; quinazolines; secondary amino compound; substituted aniline | antineoplastic agent; apoptosis inducer; epidermal growth factor receptor antagonist |
bay 869766 | |||
gilteritinib | gilteritinib : A member of the class of pyrazines that is pyrazine-2-carboxamide which is substituted by {3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}nitrilo, (oxan-4-yl)nitrilo and ethyl groups at positions 3,5 and 6, respectively. It is a potent inhibitor of FLT3 and AXL tyrosine kinase receptors (IC50 = 0.29 nM and 0.73 nM, respectively). Approved by the FDA for the treatment of acute myeloid leukemia in patients who have a FLT3 gene mutation. gilteritinib: an FLT3/AXL protein tyrosine kinase inhibitor | aromatic amine; monomethoxybenzene; N-methylpiperazine; oxanes; piperidines; primary carboxamide; pyrazines; secondary amino compound | antineoplastic agent; apoptosis inducer; EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor |
glpg0634 |