Homologous and Heterologous Desensitization Receptor

Desensitization

Homologous Desensitization

• Occurs when the same receptor activates the kinase that phosphorylates it, leading to its desensitization.
• Involves the activation of G protein-coupled receptor kinases (GRKs) directly from the receptor's activation.
• The receptor itself activates the kinase that allows its phosphorylation, leading to desensitization.

Heterologous Desensitization

• Occurs when the activation of kinases is not directly from the same receptor but indirectly through downstream signaling cascades.
• Activation of GRK comes after the cascade of signaling activated by the receptor. For example, protein kinase A (PKA) or protein kinase C (PKC) can activate GRK, which then phosphorylates the receptor.

Receptor Tyrosine Kinases (RTKs)

• Enzymatic receptors are activated by the binding of a ligand.
• Two types of receptors:
  • Receptors with intrinsic enzymatic activity: The receptor itself possesses catalytic activity in its cytoplasmic portion.
  • Receptors associated with cytosolic enzymes: The receptor activates a cytosolic enzyme upon ligand binding.
• Different enzymatic activities associated with receptors:
  • Receptor tyrosine kinase (RTK).
  • Receptor guanylyl cyclase: Activation leads to an increase in cyclic GMP.
  • Receptor serine/threonine kinase.
  • Receptor tyrosine phosphatase.
• RTKs are the most common and involve phosphorylation of tyrosine residues.
• Examples of RTKs: Various growth factor receptors and the insulin receptor.

Activation of RTKs

• RTKs typically exist as monomers and dimerize upon ligand binding.
• Dimerization brings the kinase domains of the monomers into proximity, leading to cross-phosphorylation.
• Cross-phosphorylation fully activates the receptor, allowing it to phosphorylate tyrosine residues along its cytoplasmic domain.
• The phosphorylated tyrosine residues serve as binding sites for proteins containing SH2 domains.
• Proteins that recognize these domains can bind to the receptor and become activated or phosphorylated by the receptor.
• The insulin receptor is a pre-formed dimer that undergoes a conformational change upon insulin binding, bringing the kinase domains closer for cross-phosphorylation.
• Mutations in one of the monomers that inhibits the tyrosine kinase domain prevent receptor activation, even if dimerization occurs

Downstream Signaling

• Different tyrosine residues on the receptor can bind different proteins to activate various signaling pathways.
• Tyrosine residues 740 and 751 are involved in the binding of phosphatidylinositol-3-kinase.
• Can bind a GAP protein.
• Can bind a phospholipase. Phospholipase C activation leads to the production of diacylglycerol and IP3, increasing intracellular calcium levels.
• SH2 and PTB domains recognize phosphotyrosine residues.
• The model is that phospholipase C can be activated. Phospholipase C beta was mentioned in receptors coupled to protein G. In this case, phospholipase C gamma is mentioned, but it does the same thing

Proteins with SH2 Domains

• Examples: Phospholipase C, adaptor proteins, proteins involved in endocytosis.
• Adaptor proteins can activate Ras, a monomeric G protein.
• Proteins involved in endocytosis can regulate or desensitize the cell.
• Binding domain that recognizes phosphotyrosine on the receptor.

Nerve Growth Factor (NGF) Example

• NGF, when released in the synaptic space, binds to its receptor on the neuron.
• The receptor-ligand complex is endocytosed and travels retrogradely along the axon to the soma.
• In the soma, it triggers a signaling cascade that modifies gene expression, promoting neuron survival.

RAS Proteins

• Monomeric G proteins that can be bound to either GTP (active) or GDP (inactive).
• Some RAS proteins have SH2 domains; others are activated through adaptor proteins.
• Require activation via guanine nucleotide exchange factors (GEFs) to exchange GDP for GTP.
• Some RAS proteins are activated indirectly via adaptor proteins that bind to the receptor tyrosine kinase.
• The adaptor protein binds the receptor and recruits a RasGEF, such as SOS, to activate RAS.
• Many RTKs require activation of the protein Ras
• Activated by receptors that have a tyrosine kinase enzymatic activity

Steps of Activation for Fibroblast Growth Factors

• Fibroblast growth factor binds to the receptors.
• The receptors dimerize and cross-phosphorylate.
• Phosphorylation occurs along the receptor, and proteins with SH2 domains begin to bind
• The adapter protein which has the SH2 domain will unite to this receptor.
• The possibility to unite to the Rasgef which is the Sosket (??) , and then the exchange of GDP turns into GTP and activates the RAS.

MAPK Cascade

• Ras activates the mitogen-activated protein kinase (MAPK) pathway.
• The pathway involves a series of kinases that activate each other in succession.
• MAPK kinase kinase kinase (MAPKKK or RAF) activates MAPK kinase (MAPKK or MEK), which activates MAPK (ERK).
• Activated ERK can then phosphorylate various target proteins in the cytoplasm or translocate to the nucleus to modify gene expression.
• Can modify the activity of proteins or be translocated to the nucleus

Regulation of MAPK Pathway

• The MAPK pathway is regulated by phosphatases that dephosphorylate the kinases in the cascade.
• Ras activity is regulated by RasGAPs, which promote GTP hydrolysis, inactivating Ras.
• Receptors with phosphatase activity and cytosolic phosphatases may regulate activation.
• This is important for cell proliferation, differentiation, apoptosis and senescence

RO Proteins

• In addition to Ras, RTKs can activate Rho family GTPases, which regulate the cytoskeleton.
• Activation occurs through RhoGEFs, leading to changes in cell shape and motility.
• The process of cells that grow in a single-layer replications and sense its surroundings. You can cut a portion, almost like a cut, in which they remove portions of the cell. If such is the care, the cell will register this as a wound so it will start to close that wound.
• RO, RAC, CDC 42, will activate in that order for this to happen.

Convergence of Signaling Pathways

• A single activated receptor can trigger multiple signaling cascades, such as Ras and phospholipase C.
• These pathways can converge to amplify or modulate the cellular response.