Receptor Signalling 2

Question 1

What are Receptor Tyrosine Kinases (RTKs) and how many families do they belong to?

Answer 1

Receptor Tyrosine Kinases (RTKs) are cell surface receptors that possess intrinsic kinase activity. There are over 50 RTKs classified into 14 families.

Question 2

What is the role of RTKs and their associated signaling pathways in cellular processes?

Answer 2

RTKs and their signaling pathways play a pivotal role in controlling cellular growth, proliferation, and differentiation

Question 3

Name some ligands that activate Receptor Tyrosine Kinases (RTKs)

Answer 3

Ligands that activate RTKs include various growth factors (GF) such as Fibroblast GF (FGF), Vascular endothelial GF (VEGF), Platelet-derived GF (PDGF), Epidermal GF (EGF), and Hepatocyte GF

Question 4

Which specific receptor is mentioned as an example of a kinase-linked receptor?

Answer 4

The insulin receptor is an example of a kinase-linked receptor.

Question 5

What is the basic structure of a kinase-linked receptor (RTK)?

Answer 5

Kinase-linked receptors have an extracellular domain and an intracellular domain connected by a single α-helix that spans the cell membrane

Question 6

Where are kinase-linked receptors (RTKs) found?

Answer 6

Kinase-linked receptors are found embedded in cell membranes.

Question 7

How many amino acid residues are typically present in each domain of a kinase-linked receptor?

Answer 7

Each domain of a kinase-linked receptor contains 400-700 amino acid residues.

Question 8

How are the extracellular and intracellular domains of a kinase-linked receptor connected?

Answer 8

They are connected together by a single α-helix that spans the cell membrane.

Question 9

What is the basic structure of a kinase-linked receptor (RTK)?

Answer 9

The extracellular domain of a kinase-linked receptor contains the receptor’s ligand-binding site.
The amino acid sequences in this extracellular domain vary greatly among different kinase-linked receptors, providing ligand selectivity.

Question 10

What is notable about the intracellular domains of kinase-linked receptors (RTKs)?

Answer 10

The intracellular domains of kinase-linked receptors are more conserved compared to the extracellular domains.
The region closest to the membrane in the intracellular domain contains a binding site for ATP, crucial for the receptor’s kinase activity.

Question 11

What is the basic structure of a kinase-linked receptor (RTK)?

Answer 11

A kinase-linked receptor (RTK) consists of an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular domain (cytoplasmic tail) that possesses intrinsic tyrosine kinase activity.

Question 12

What is the function of the intracellular domain (cytoplasmic tail) of a kinase-linked receptor (RTK)?

Answer 12

The intracellular domain of a kinase-linked receptor (RTK) possesses intrinsic tyrosine kinase activity, which means it can phosphorylate (add phosphate groups to) specific tyrosine residues on proteins inside the cell.

Question 13

What role do kinase enzymes play in cellular signaling?

Answer 13

Kinase enzymes are responsible for catalyzing the phosphorylation (addition of phosphate groups) of various cellular components, including other proteins. This phosphorylation is a key step in many signaling pathways that regulate cell growth, differentiation, and metabolism.

Question 14

Where do kinase enzymes get the phosphate groups needed for phosphorylation?

Answer 14

The phosphate groups used by kinase enzymes for phosphorylation come from ATP (adenosine triphosphate) molecules. ATP molecules are bound to the intracellular domains of kinase-linked receptors, providing a source of phosphate groups for enzymatic reactions.

Question 15

What is the structural reason why ligand binding to the extracellular domain of certain receptors does not directly cause a conformational change throughout the entire receptor molecule?

Answer 15

Only a simple α-helix connects the extracellular domain to the rest of the receptor molecule, which prevents propagation of conformational changes.

Question 16

What process occurs instead of a direct conformational change upon ligand binding to certain receptors?

Answer 16

Dimerization of receptors occurs, where two receptor molecules pair up (form a dimer) upon ligand binding.

Question 17

Define dimerization in the context of receptor activation.

Answer 17

Dimerization refers to the process where two receptor molecules bind to each other (pair up) upon ligand binding, leading to activation of downstream signaling pathways

Question 18

How does ligand binding to the extracellular domain initiate receptor activation in receptors with a simple α-helix connection?

Answer 18

Ligand binding promotes dimerization of receptors, which triggers intracellular signaling cascades without a direct conformational change in the receptor structure.

Question 19

What is the initial step in receptor activation?

Answer 19

Ligand binding to the receptor initiates the process of receptor activation.

Question 20

What is contained within the intracellular domain of certain receptors?

Answer 20

The intracellular domain of certain receptors contains tyrosine residues.

Question 21

What happens when receptor dimers form?

Answer 21

When receptor dimers form, a process called ‘autophosphorylation’ occurs.

Question 22

What is ‘autophosphorylation’?

Answer 22

‘Autophosphorylation’ is a process where tyrosine residues in the receptor’s intracellular domain become phosphorylated.

Question 23

Where do the phosphate groups come from during autophosphorylation?

Answer 23

The phosphate groups used in autophosphorylation are donated by bound ATP (adenosine triphosphate)

Question 24

What are the high affinity binding sites on receptor tyrosine kinases for intracellular proteins following signal transduction?

Answer 24

Phosphotyrosine residues serve as high affinity binding sites for intracellular proteins during signal transduction.

Question 25

What type of domains do the intracellular proteins contain that interact with phosphotyrosine residues on receptor tyrosine kinases?

Answer 25

The interacting proteins contain SH2 domains (~100 amino acid residues) that bind specifically to phosphorylated tyrosine residues on the receptor

Question 26

What is the origin of the name “SH2” for the domains that bind to phosphotyrosine residues?

Answer 26

SH2 domains are named after “Src-homology,” as they were initially identified in the Src oncogene

Question 27

What happens to the bound intracellular protein upon interaction with phosphotyrosine residues on receptor tyrosine kinases?

Answer 27

The bound protein becomes activated, initiating a cellular response.

Question 28

What was the discovery related to transformation of cells into tumor cells by the Rous sarcoma virus?

Answer 28

Infection with the Rous sarcoma virus led to cell transformation due to the expression of a single viral gene, V-src.

Question 29

What is the structural arrangement of the SH2 domain?

Answer 29

The SH2 domain consists of a central anti-parallel β-pleated sheet surrounded by two α helices.

Question 30

What key residue in the SH2 domain coordinates phosphotyrosine binding?

Answer 30

Arginine (Arg) residue in the SH2 domain coordinates phosphotyrosine binding.

Question 31

Describe the interaction of the SH2 domain of v-src with a PY peptide ligand.

Answer 31

The SH2 domain of v-src binds to a PY (phosphotyrosine) peptide ligand, demonstrating specific recognition of phosphotyrosine-containing sequences.

Question 32

What should RTKs be considered as, besides receptors with intrinsic enzyme activity?

Answer 32

RTKs should be considered as platforms for recognition and recruitment of a specific complement of signaling proteins.

Question 33

What is the structure of the insulin receptor?

Answer 33

The insulin receptor is a complex consisting of two α-subunits and two β-subunits, held together by disulfide bridges. The α-subunits are located extracellularly, while the β-subunits are transmembrane spanning proteins. The α-subunits form the insulin binding site, while the intracellular portion of the β-subunits possesses intrinsic tyrosine kinase activity.

Question 34

What happens when insulin binds to the insulin receptor?

Answer 34

Insulin binding promotes auto-phosphorylation of Tyr residues on the intracellular domains of the insulin receptor.

Question 35

What occurs rapidly after insulin binding to the insulin receptor?

Answer 35

Rapid phosphorylation of adaptor proteins also occurs.

Question 36

What is the best-characterized substrate of the insulin receptor?

Answer 36

The best-characterized substrate is IRS-1 (insulin receptor substrate-1), which contains 22 tyrosine residues.

Question 37

How do phosphorylated Tyr residues on IRS-1 act?

Answer 37

Phosphorylated Tyr residues act as docking sites for a repertoire of signaling proteins which contain SH2 domains

Question 38

What is insulin?

Answer 38

Insulin is a polypeptide hormone with a molecular weight of approximately 6,000. It is produced in the islets of Langerhans in the pancreas

Question 39

What is the role of insulin?

Answer 39

Insulin plays a crucial role in regulating blood glucose levels. It helps lower high blood sugar levels by promoting the uptake of glucose into cells for energy production and storage.

Question 40

Where is insulin produced?

Answer 40

Insulin is produced in the islets of Langerhans, specialized regions within the pancreas

Question 41

What stimulates the secretion of insulin?

Answer 41

High blood sugar levels stimulate the secretion of insulin. When blood glucose levels rise, it triggers the release of insulin from pancreatic beta cells to help bring glucose levels back to normal.

Question 42

What are the short-term actions triggered by activated insulin receptors?

Answer 42

The short-term actions include recruiting glucose receptors, increasing glucose uptake into cells, enhancing glycogen synthesis, and decreasing both gluconeogenesis and glycogen breakdown. These immediate metabolic effects are generally regulated by kinase and phospholipase enzymes.

Question 43

Describe the cellular events associated with activated insulin receptors.

Answer 43

Cellular events triggered by activated insulin receptors involve both short-term and long-term actions. In the short term, insulin recruits glucose receptors, increases glucose uptake into cells, promotes glycogen synthesis, and inhibits both gluconeogenesis and glycogen breakdown. These effects are primarily mediated by regulating kinase and phospholipase enzymes.

Question 44

What percentage of insulin receptors need to be occupied to evoke a maximum response?

Answer 44

Less than 10% of insulin receptors need to be occupied.

Question 45

What happens when insulin binds to its receptor?

Answer 45

Clusters of ligand/receptor complexes form, which are then internalized in vesicles.

Question 46

What occurs in insulin resistance?

Answer 46

In insulin resistance, tissues become unresponsive to insulin due to bombardment of their insulin receptors with elevated blood insulin levels. This leads to down-regulation of the receptor (loss of insulin receptors from the cell surface) and impaired signaling mechanisms that recruit the transporter GLUT-4.

Question 47

What cellular events are triggered by activated insulin receptors?

Answer 47

Cellular events triggered by activated insulin receptors have both short- and long-term actions.

Question 48

How does insulin receptor activation signal to the nucleus?

Answer 48

Insulin receptor activation signals to the nucleus via a series of signal transduction proteins to promote gene expression.

Question 49

What are the two main purposes of insulin receptor signaling to the nucleus?

Answer 49

Insulin receptor signaling to the nucleus serves to:

1.Modulate the synthesis of key enzymes involved in the regulation of blood glucose.
2.Promote cell growth and division.

Question 50

What are nuclear receptors?

Answer 50

Nuclear receptors are intracellular receptors that regulate gene expression. They are not expressed on cell membranes.

Question 51

Where are nuclear receptors located?

Answer 51

Nuclear receptors are located inside the cell, not on cell membranes

Question 52

What is the role of nuclear receptors?

Answer 52

Nuclear receptors regulate gene expression by binding to specific ligands and influencing the transcription of DNA into mRNA, which ultimately leads to the production of proteins.

Question 53

What types of ligands bind to nuclear receptors?

Answer 53

Ligands for nuclear receptors include steroid hormones (e.g., estrogen, testosterone), thyroid hormone, vitamin D, retinoic acid, and other agents that regulate gene expression.

Question 54

What is the primary mode of distribution for hormones in the body?

Answer 54

Hormones are produced by endocrine glands and distributed throughout the body via the bloodstream, where they bind to specific receptors.

Question 55

Where are hormones produced and how are they distributed in the body?

Answer 55

Hormones are produced by endocrine glands and released into the bloodstream to be distributed throughout the body, where they bind to target receptors to initiate physiological responses.

Question 56

Give examples of hormones and their sources.

Answer 56

Examples of hormones include sex hormones such as estrogen and testosterone, which are produced by the ovaries and testes, respectively, as well as other hormones like insulin (produced by the pancreas) and thyroid hormones (produced by the thyroid gland).

Question 57

What is the primary mode of transmission for neurotransmitters in the nervous system?

Answer 57

Neurotransmitters are released from neuron terminals and transmit action potential signals across synapses to target cells.

Question 58

Where are neurotransmitters released from and how do they transmit signals?

Answer 58

Neurotransmitters are released from neuron terminals and transmit signals across synapses to target cells, facilitating communication between neurons and other cells in the nervous system

Question 59

Provide examples of neurotransmitters and their functions.

Answer 59

Examples of neurotransmitters include acetylcholine, which is involved in muscle contraction and memory formation, and noradrenaline, which plays a role in the body’s stress response and regulation of mood.

Question 60

What is the basic structure of nuclear receptors?

Answer 60

Nuclear receptors are large monomeric proteins consisting of 400-1000 amino acid residues. The middle portion contains two finger-shaped loops of peptide chain, each about 15 residues long. These loops are called “zinc fingers” because they contain a Zn2+ ion.

Question 61

What is the function of the carboxyl end of the receptor?

Answer 61

The carboxyl end contains the steroid binding domain.

Question 62

Which region of the receptor forms the DNA binding region?

Answer 62

The zinc finger region forms the DNA binding region.

Question 63

What is the function of the amino end of the receptor?

Answer 63

The amino end is the receptor’s regulatory domain that can activate the transcription of specific genes.

Question 64

What is the mechanism of action for steroid hormones and drugs in triggering gene transcription?

Answer 64

Steroid hormones and drugs operate by binding to nuclear receptors, which then translocate to the nucleus and bind to specific DNA sequences, initiating the transcription of target genes and leading to the synthesis of proteins.

Question 65

Why do the ligands of nuclear receptors need to be lipid soluble?

Answer 65

The ligands of nuclear receptors need to be lipid soluble in order to pass through the cell’s plasma membrane and gain access to the intracellular compartment where the receptors are located

Question 66

How do steroid molecules gain access to the intracellular compartment to bind to their receptors?

Answer 66

Steroid molecules are highly lipid soluble, allowing them to easily pass through the cell’s plasma membrane and reach the intracellular compartment where they can bind to their receptors located in the nucleus.

Question 67

What conformational change occurs when a steroid binds to its receptor?

Answer 67

The steroid receptor unfolds to expose the zinc finger domain.

Question 68

What happens once the ligand/receptor complex is formed?

Answer 68

The complex can bind to specific portions of DNA

Question 69

What are the specific regions of DNA that the ligand/receptor complex binds to?

Answer 69

Hormone responsive elements

Question 70

Where are hormone responsive elements located in relation to the regulated genes?

Answer 70

They are approximately 200 DNA base pairs upstream from the regulated genes.

Question 71

What happens within minutes of the ligand/receptor complex binding to DNA?

Answer 71

Within minutes of the ligand/receptor complex binding to DNA, there is an increase in RNA polymerase activity.

Question 72

What is the result of the increase in RNA polymerase activity?

Answer 72

The result of the increase in RNA polymerase activity is the production of mRNA.

Question 73

What occurs after mRNA is produced?

Answer 73

After mRNA is produced, it leaves the nucleus to form a complex with ribosomes.

Question 74

What does the complex of mRNA with ribosomes enable?

Answer 74

The complex of mRNA with ribosomes enables the synthesis of new proteins.

Question 75

Why may the actual physiological responses be delayed by several hours or even days?

Answer 75

The actual physiological responses may be delayed by several hours or even days because the whole process relies on protein synthesis.

Question 76

What are the agents that bind to nuclear receptors and interact with DNA to modify gene transcription?

Answer 76

Glucocorticoids, mineralocorticoids, sex hormones, thyroid hormones, vitamin D3, and retinoic acid.

Question 77

Which types of hormones can bind to nuclear receptors and influence gene transcription?

Answer 77

Glucocorticoids, mineralocorticoids, sex hormones, thyroid hormones, vitamin D3, and retinoic acid.

Question 78

Where are receptors for glucocorticoids found in the body?

Answer 78

Receptors for glucocorticoids are found in almost every type of tissue.

Question 79

How many genes of each cell are steroid responsive, depending on the cell type?

Answer 79

It is thought that between 10-100 genes of each cell are steroid responsive, depending on the cell type

Question 80

What is the mechanism of action of glucocorticoid receptors?

Answer 80

Glucocorticoid receptors bind intracellularly, dimerize, migrate to the nucleus, and interact with DNA to modify gene transcription and protein synthesis. They induce the synthesis of some anti-inflammatory proteins and inhibit the synthesis of inflammatory proteins.