Week 32 /Kinase-linked Receptors

Question 1

Q: What defines a receptor superfamily?

Answer 1

A: A receptor superfamily is a group of receptors that share a similar molecular structure and use the same signal transduction pathway.

Question 2

Q: What are the four major receptor superfamilies?

Answer 2

A:

Ligand-gated/Ion channel-linked receptors

G-protein-coupled receptors

Kinase-linked receptors

Intracellular/Nuclear receptors

Question 3

Q: What are enzyme-linked receptors?

Answer 3

A: Enzyme-linked receptors are a superfamily of transmembrane receptor protein complexes that either:

Contain an intrinsic enzyme activity in their intracellular domain, or

Associate directly with an intracellular enzyme.

Question 4

Q: What happens when a ligand binds to an enzyme-linked receptor?

Answer 4

A:

Ligand binding → conformational change in the receptor

Signal is transmitted via a transmembrane helix

This leads to activation of an intrinsic or associated enzyme

Initiates signaling cascades

Question 5

Q: What biological functions do enzyme-linked receptors regulate?

Answer 5

A:

Mediate actions of growth factors, cytokines, and hormones

Regulate cell growth, proliferation, and differentiation

Question 6

Q: What are the five main types of enzyme-linked receptors?

Answer 6

A:

Receptor Tyrosine Kinases (RTKs) – Contain intrinsic tyrosine kinase activity (e.g., EGFR, IR)

Receptor Serine/Threonine Kinases – Contain intrinsic serine/threonine kinase activity (e.g., TGF-βR)

Tyrosine Kinase-Associated Receptors (Cytokine Receptors) – Associate with proteins that have tyrosine kinase activity

Receptor Guanylyl Cyclases – Contain intrinsic guanylyl cyclase activity (e.g., ANPR)

Receptor Tyrosine Phosphatases – Have intrinsic phosphatase activity

Question 7

Q: What distinguishes receptor tyrosine kinases (RTKs) from tyrosine kinase-associated receptors?

Answer 7

A:

RTKs have intrinsic tyrosine kinase activity within their intracellular domain.

Tyrosine kinase-associated receptors lack intrinsic enzyme activity but associate with intracellular tyrosine kinases.

Question 8

Q: What are receptor tyrosine kinases (RTKs)?

Answer 8

A: RTKs are cell-surface receptors that mediate the actions of polypeptide and protein hormones and growth factors. They contain an intrinsic tyrosine kinase domain that becomes active upon ligand binding, initiating signaling cascades.

Question 9

Q: How many RTKs are found in the human genome, and how are they classified?

Answer 9

A: 58 RTKs have been identified in the human genome and are classified into 20 families (Type I–XX).

Question 10

Q: How are RTKs linked to disease?

Answer 10

A: Mutations in RTKs are implicated in many diseases, including various human cancers.

Question 10

Q: Which RTK family is most commonly studied?

Answer 10

A: The Type I RTK family, which includes the Epidermal Growth Factor Receptor (EGFR) family.

Question 10

Q: What are the key cellular processes regulated by RTKs?

Answer 10

A:

Proliferation & differentiation

Cell survival & metabolism

Cell migration

Cell cycle control

Question 11

Q: What key cellular functions do EGFRs regulate?

Answer 11

A: EGFRs regulate cell proliferation, differentiation, growth, survival, and migration.

Question 12

Q: What peptide growth factors activate EGFRs?

Answer 12

A: Epidermal Growth Factor (EGF) and Transforming Growth Factor-α (TGF-α) activate EGFRs.

Question 13

Q: Where is EGF synthesized and released from?

Answer 13

A: EGF is synthesized and released from the kidney, submaxillary gland, and other organs.

Question 14

Q: What are some biological processes promoted by EGFR signaling?

Answer 14

A:

Embryonic development

Stem cell regeneration

Regulation of ion transport

Wound healing

Question 15

Q: How is EGFR dysregulation linked to cancer?

Answer 15

A: EGFR mutations and overexpression contribute to cancer development, leading to uncontrolled cell growth and proliferation.

Question 16

Q: What are the main structural components of EGFRs?

Answer 16

A:

Extracellular ligand-binding domain

Single transmembrane (TM) helix domain

Juxtamembrane region

Intracellular tyrosine kinase domain (TKD)

Adaptor domains with tyrosine residues

Flexible C-terminal tail

Question 17

Q: What happens when EGF binds to EGFR?

Answer 17

A: EGFR monomers dimerize, leading to a conformational change that releases cis-autoinhibition.

Question 18

Q: What is the result of EGFR dimerization?

Answer 18

A: It triggers trans- and autophosphorylation of tyrosine residues in the cytoplasmic domains.

Question 19

Q: Why are phosphorylated tyrosine residues important in EGFR signaling?

Answer 19

A: They serve as a platform for the recruitment of multiple adaptor/effector proteins, initiating downstream signaling cascades.

Question 20

Q: What are the two main downstream signaling pathways activated by EGFRs?

Answer 20

A: The RAS/MAPK and PI3K/AKT signaling pathways.

Question 21

Q: What is the main function of the RAS/MAPK pathway?

Answer 21

A: It regulates cell proliferation, differentiation, and survival.

Question 22

Q: What is the main function of the PI3K/AKT pathway?

Answer 22

A: It promotes cell survival, growth, and metabolism by inhibiting apoptosis.

Question 23

Q: What happens when EGFR is activated?

Answer 23

A: EGFR dimerizes, leading to tyrosine autophosphorylation, which serves as a docking site for signaling proteins that activate RAS/MAPK and PI3K/AKT pathways.

Question 24

Q: How is RAS activated in the RAS/MAPK pathway?

Answer 24

A: Grb2 binds to activated EGFR, recruiting and activating the guanine nucleotide exchange factor SOS, which exchanges GDP for GTP on RAS, activating it.

Question 25

Q: What is the role of RAS-GTP in the RAS/MAPK pathway?

Answer 25

A: RAS-GTP activates RAF kinase (MAPKKK), which in turn activates MEK 1/2 (MAPKK).

Question 25

Q: How is PI3K recruited to the plasma membrane in the PI3K/AKT pathway?

Answer 25

A: Grb2 associates with Gab1, recruiting PI3K to the plasma membrane, where it phosphorylates PIP2 to generate PIP3.

Question 26

Q: What does MEK 1/2 (MAPKK) activate in the RAS/MAPK pathway?

Answer 26

A: MEK 1/2 (MAPKK) activates ERK 1/2 (MAPK).

Question 26

Q: What happens after ERK 1/2 (MAPK) is activated in the RAS/MAPK pathway?

Answer 26

A: ERK 1/2 (MAPK) phosphorylates critical effector proteins in the cytoplasm and translocates to the nucleus, where it phosphorylates transcription factors like CREB, ELK-1, c-Fos, and c-Jun, promoting cell growth, proliferation, differentiation, and survival.

Question 27

Q: What happens after the accumulation of PIP3 in the PI3K/AKT pathway?

Answer 27

A: PIP3 co-localizes with Akt/Protein Kinase B (PKB) and PDK1, allowing for their activation.

Question 28

Q: How is AKT/PKB activated in the PI3K/AKT pathway?

Answer 28

A: AKT/PKB is phosphorylated by both PDK1 and mTORC2 on the plasma membrane.

Question 28

Q: What is the function of cytokine receptors?

Answer 28

A: Cytokine receptors transduce signals from cytokines, which are small proteins that facilitate cell communication and play essential roles in cell development, differentiation, and immune/inflammatory responses.

Question 28

Q: What is the role of activated AKT in the PI3K/AKT pathway?

Answer 28

A: Activated AKT translocates to the cytosol and phosphorylates critical target proteins, regulating cell growth, proliferation, motility, neovascularization, and cell death.

Question 29

Q: What role do Janus Kinases (JAKs) play in cytokine receptor signaling?

Answer 29

A: JAKs are intracellular kinases that convert extracellular stimuli into a wide range of cellular processes through the JAK/STAT pathway.

Question 29

Q: How do many cytokine receptors work?

Answer 29

A: Many cytokine receptors associate directly with intracellular non-receptor tyrosine protein kinases to mediate signal transduction.

Question 30

Q: What are STATs in cytokine receptor signaling?

Answer 30

A: STATs are a family of transcription factors and SH2-domain proteins that are activated by JAKs and mediate the expression of genes related to immune function, growth, and differentiation.

Question 31

Q: How are JAKs activated in the JAK/STAT pathway?

Answer 31

A: JAKs are activated through transphosphorylation, where they phosphorylate specific tyrosine residues in the cytoplasmic domains of the cytokine receptor chains.

Question 31

Q: What initiates the JAK/STAT signaling pathway?

Answer 31

A: The binding of a cytokine to its receptor, which leads to receptor dimerization and the activation of associated JAKs.

Question 32

Q: What happens after STATs dock to the phosphorylated receptor chains?

Answer 32

A: Once STATs dock on the receptor chains, they are phosphorylated by the JAKs, become activated, and dissociate from the receptor chains.

Question 33

Q: What occurs after phosphorylated STATs dissociate from the receptor?

Answer 33

A: The phosphorylated STATs dimerize, translocate to the cell nucleus, and activate gene transcription, leading to the production of proteins involved in immune responses and inflammation.

Question 34

Q: What is the final outcome of the JAK/STAT pathway?

Answer 34

A: The activation of transcription and translation results in the production of proteins that mediate immune responses and inflammation, completing the inflammation feedback loop.

Question 35

Q: How do EGFR and its signaling pathways contribute to human cancers?

Answer 35

A: EGFR and its signaling pathways play key roles in the development of fibro-sarcomas, glioblastomas, mammary, ovarian, colorectal, and non-small cell lung cancer through mechanisms such as mutation, overexpression, abnormal constitutive activity, or increased autocrine signaling.

Question 36

Q: What is the cause of oncogenic transformation in relation to EGFR?

Answer 36

A: Oncogenic transformation can result from the loss of auto-control mechanisms of EGFR, which may involve mutations, overexpression of the receptor, abnormal constitutive receptor activity, or increased autocrine signaling.

Question 37

Q: What are the two major classes of EGFR-targeted anticancer therapies?

Answer 37

A: The two major classes of EGFR-targeted therapies are: Humanized monoclonal antibodies (e.g., cetuximab, panitumumab) that block ligand binding to EGFR. Tyrosine kinase inhibitors (TKIs) (e.g., erlotinib, gefitinib, lapatinib) that bind to the receptor’s kinase pocket to prevent signal transduction.

Question 38

Q: How do tyrosine kinase inhibitors (TKIs) work in treating cancer?

Answer 38

A: TKIs are ATP mimetics that bind to the EGFR kinase pocket, preventing ATP binding and signal transduction, ultimately blocking the downstream oncogenic signaling pathways.

Question 39

Q: How do monoclonal antibodies like cetuximab and panitumumab work?

Answer 39

A: Humanized monoclonal antibodies such as cetuximab and panitumumab target the extracellular domain of EGFR, blocking the binding of ligands (like EGF), thus inhibiting receptor activation and downstream signaling.

Question 40

Q: What role does dysregulation of cytokine receptor-stimulated JAK/STAT signaling play in diseases?

Answer 40

A: Dysregulation of cytokine receptor-stimulated JAK/STAT signaling is implicated in the development of various human cancers and immune/inflammatory disorders such as rheumatoid arthritis, atopic dermatitis, psoriasis, and inflammatory bowel disease.

Question 41

Q: What happens when JAK/STAT signaling is dysregulated?

Answer 41

A: Dysregulation of JAK/STAT signaling leads to increased JAK & STAT activity and decreased activity of intrinsic negative regulators, resulting in upregulation of pro-proliferative, anti-apoptotic, pro-inflammatory, and immunosuppressive proteins.

Question 42

Q: How do JAK inhibitors help in treating immune/inflammatory disorders?

Answer 42

A: JAK inhibitors help by reducing the activity of JAKs, which decreases pro-inflammatory signaling and restores balance in immune responses, thus treating disorders like rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

Question 43

Q: What are some examples of JAK inhibitors used in the treatment of inflammatory disorders?

Answer 43

A: Some examples of JAK inhibitors include: Tofacitinib (JAK1, 2 & 3 inhibitor) - used for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Baricitinib (JAK1 & 2 inhibitor), Filgotinib, Upadacitinib (JAK1 inhibitors) - used for rheumatoid/psoriatic arthritis, inflammatory bowel disease (IBD). Ruxolitinib (JAK1 & 2 inhibitor) - used for polycythemia and myelofibrosis.

Question 44

Q: What diseases are associated with increased JAK & STAT activity?

Answer 44

A: Increased JAK & STAT activity is associated with diseases like rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), and certain human cancers.