Week 32 /Kinase-linked Receptors Flashcards
Q: What defines a receptor superfamily?
A: A receptor superfamily is a group of receptors that share a similar molecular structure and use the same signal transduction pathway.
Q: What are the four major receptor superfamilies?
A:
Ligand-gated/Ion channel-linked receptors
G-protein-coupled receptors
Kinase-linked receptors
Intracellular/Nuclear receptors
Q: What are enzyme-linked receptors?
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.
Q: What happens when a ligand binds to an enzyme-linked receptor?
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
Q: What biological functions do enzyme-linked receptors regulate?
A:
Mediate actions of growth factors, cytokines, and hormones
Regulate cell growth, proliferation, and differentiation
Q: What are the five main types of enzyme-linked receptors?
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
Q: What distinguishes receptor tyrosine kinases (RTKs) from tyrosine kinase-associated receptors?
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.
Q: What are receptor tyrosine kinases (RTKs)?
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.
Q: How many RTKs are found in the human genome, and how are they classified?
A: 58 RTKs have been identified in the human genome and are classified into 20 families (Type I–XX).
Q: How are RTKs linked to disease?
A: Mutations in RTKs are implicated in many diseases, including various human cancers.
Q: Which RTK family is most commonly studied?
A: The Type I RTK family, which includes the Epidermal Growth Factor Receptor (EGFR) family.
Q: What are the key cellular processes regulated by RTKs?
A:
Proliferation & differentiation
Cell survival & metabolism
Cell migration
Cell cycle control
Q: What key cellular functions do EGFRs regulate?
A: EGFRs regulate cell proliferation, differentiation, growth, survival, and migration.
Q: What peptide growth factors activate EGFRs?
A: Epidermal Growth Factor (EGF) and Transforming Growth Factor-α (TGF-α) activate EGFRs.
Q: Where is EGF synthesized and released from?
A: EGF is synthesized and released from the kidney, submaxillary gland, and other organs.
Q: What are some biological processes promoted by EGFR signaling?
A:
Embryonic development
Stem cell regeneration
Regulation of ion transport
Wound healing
Q: How is EGFR dysregulation linked to cancer?
A: EGFR mutations and overexpression contribute to cancer development, leading to uncontrolled cell growth and proliferation.
Q: What are the main structural components of EGFRs?
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
Q: What happens when EGF binds to EGFR?
A: EGFR monomers dimerize, leading to a conformational change that releases cis-autoinhibition.
Q: What is the result of EGFR dimerization?
A: It triggers trans- and autophosphorylation of tyrosine residues in the cytoplasmic domains.
Q: Why are phosphorylated tyrosine residues important in EGFR signaling?
A: They serve as a platform for the recruitment of multiple adaptor/effector proteins, initiating downstream signaling cascades.
Q: What are the two main downstream signaling pathways activated by EGFRs?
A: The RAS/MAPK and PI3K/AKT signaling pathways.
Q: What is the main function of the RAS/MAPK pathway?
A: It regulates cell proliferation, differentiation, and survival.
Q: What is the main function of the PI3K/AKT pathway?
A: It promotes cell survival, growth, and metabolism by inhibiting apoptosis.
Q: What happens when EGFR is activated?
A: EGFR dimerizes, leading to tyrosine autophosphorylation, which serves as a docking site for signaling proteins that activate RAS/MAPK and PI3K/AKT pathways.
Q: How is RAS activated in the RAS/MAPK pathway?
A: Grb2 binds to activated EGFR, recruiting and activating the guanine nucleotide exchange factor SOS, which exchanges GDP for GTP on RAS, activating it.
Q: What is the role of RAS-GTP in the RAS/MAPK pathway?
A: RAS-GTP activates RAF kinase (MAPKKK), which in turn activates MEK 1/2 (MAPKK).
Q: How is PI3K recruited to the plasma membrane in the PI3K/AKT pathway?
A: Grb2 associates with Gab1, recruiting PI3K to the plasma membrane, where it phosphorylates PIP2 to generate PIP3.
Q: What does MEK 1/2 (MAPKK) activate in the RAS/MAPK pathway?
A: MEK 1/2 (MAPKK) activates ERK 1/2 (MAPK).
Q: What happens after ERK 1/2 (MAPK) is activated in the RAS/MAPK pathway?
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.
Q: What happens after the accumulation of PIP3 in the PI3K/AKT pathway?
A: PIP3 co-localizes with Akt/Protein Kinase B (PKB) and PDK1, allowing for their activation.
Q: How is AKT/PKB activated in the PI3K/AKT pathway?
A: AKT/PKB is phosphorylated by both PDK1 and mTORC2 on the plasma membrane.
Q: What is the function of cytokine receptors?
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.
Q: What is the role of activated AKT in the PI3K/AKT pathway?
A: Activated AKT translocates to the cytosol and phosphorylates critical target proteins, regulating cell growth, proliferation, motility, neovascularization, and cell death.
Q: What role do Janus Kinases (JAKs) play in cytokine receptor signaling?
A: JAKs are intracellular kinases that convert extracellular stimuli into a wide range of cellular processes through the JAK/STAT pathway.
Q: How do many cytokine receptors work?
A: Many cytokine receptors associate directly with intracellular non-receptor tyrosine protein kinases to mediate signal transduction.
Q: What are STATs in cytokine receptor signaling?
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.
Q: How are JAKs activated in the JAK/STAT pathway?
A: JAKs are activated through transphosphorylation, where they phosphorylate specific tyrosine residues in the cytoplasmic domains of the cytokine receptor chains.
Q: What initiates the JAK/STAT signaling pathway?
A: The binding of a cytokine to its receptor, which leads to receptor dimerization and the activation of associated JAKs.
Q: What happens after STATs dock to the phosphorylated receptor chains?
A: Once STATs dock on the receptor chains, they are phosphorylated by the JAKs, become activated, and dissociate from the receptor chains.
Q: What occurs after phosphorylated STATs dissociate from the receptor?
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.
Q: What is the final outcome of the JAK/STAT pathway?
A: The activation of transcription and translation results in the production of proteins that mediate immune responses and inflammation, completing the inflammation feedback loop.
Q: How do EGFR and its signaling pathways contribute to human cancers?
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.
Q: What is the cause of oncogenic transformation in relation to EGFR?
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.
Q: What are the two major classes of EGFR-targeted anticancer therapies?
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.
Q: How do tyrosine kinase inhibitors (TKIs) work in treating cancer?
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.
Q: How do monoclonal antibodies like cetuximab and panitumumab work?
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.
Q: What role does dysregulation of cytokine receptor-stimulated JAK/STAT signaling play in diseases?
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.
Q: What happens when JAK/STAT signaling is dysregulated?
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.
Q: How do JAK inhibitors help in treating immune/inflammatory disorders?
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.
Q: What are some examples of JAK inhibitors used in the treatment of inflammatory disorders?
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.
Q: What diseases are associated with increased JAK & STAT activity?
A: Increased JAK & STAT activity is associated with diseases like rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), and certain human cancers.
