Week 3 Flashcards
What does tyrosine phosphorylation do?
Protein tyrosine phosphorylation (PTP) is an important posttranslational modification that controls the cell signaling involved in the regulation of a variety of biological processes, including cell growth, proliferation, differentiation, migration, survival, and death
What is the relationship between RTKs and adapter proteins?
Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs
What is Ret mutation?
The most common genetic cause of Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine.
What is the link between the RET gene and disease?
Mutations in the RET gene are the most common genetic cause of Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. More than 200 RET gene mutations are known to cause this condition.
What are the main functions of GPCRS?
Mediate most cellular responses to hormones and neurotransmitters, as well as being responsible for vision, olfaction and taste.
What second messengers do GPCRs send signals to?
Cyclic AMP (cAMP) exclusively from the plasma membrane
What do drugs that target GPCRs include?
Both agonists and antagonists that are used in the treatment of diseases of nearly every major organ system, including the central nervous system (CNS), cardiovascular, respiratory, metabolic and urogenital systems
How do GPCRs work in cancer?
Modulate the processes such as proliferative signaling, replicative immortality, evasion of growth suppressors, resistance to apoptosis, initiation of angiogenesis, and activation of invasion and metastasis that are identified as the hallmarks of cancer
What is cell surface receptor signaling pathway?
The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor
What causes cancer?
Damage to the DNA in your cells.
What is a tumour suppressor gene?
Gene that regulates a cell during cell division and replication
What are the four major mechanisms of tumour suppressor loss?
- inhibition of cell division
- induction of apoptosis
- DNA damage repair
- inhibition of metastasis.
What are proto-oncogenes?
A group of genes that cause normal cells to become cancerous when they are mutated
What is the role of oncogene?
They regulate cell proliferation, growth, and differentiation, as well as control of the cell cycle and apoptosis.
What does oncogene addiction describe?
The dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties, despite the likely accumulation of multiple gain- and loss-of-function mutations
What do cancer cells do to tyrosine kinases?
Blocking them may help keep cancer cells from growing
What does the EGFR family play a role in?
Regulating cell proliferation, survival, differentiation and migration
What does the loss of EGFR receptor regulation underlie?
Many human diseases, most notably cancer
How is EGFR activated?
According to the “ligand-induced dimerization model”, EGFR is activated by the ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation to initiate downstream signaling cascades.
What is EGFR dimerisation?
Dimerization is essential to enable the intracellular kinase domain of EGFR to become activated.
How does EGFR signal?
Epidermal growth factor receptor (EGFR) signaling pathways leading to G1/S cell cycle progression activated by EGF activation.
How does the adaptor protein Grb2 function?
Binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades.
What are pseudokinases?
The catalytically defective counterparts of conventional, active protein kinases and have been attributed functions as protein interaction domains acting variously as allosteric modulators of conventional protein kinases and other enzymes, as regulators of protein trafficking or localisation, as hubs to nucleate assembly of signalling complexes, and as transmembrane effectors of such functions
What does the subcellular localisation of RAS GTPases define?
The operational compartment of the EGFR-ERK1/2 signaling pathway within cells
What pathways are activated with EGFR?
The RAS/RAF/MAPK, AKT, and JAK/STAT pathways downstream of EGFR play integral roles in cell migration, proliferation, and survival, respectively.
What is the combination of anti-EGFR and MEK inhibitor able to prevent?
The onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines
What is EGFR?
A transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands
How is EGFR signalling turned off?
By blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity
What is the role of PTP1B?
Its purpose is to downregulate EGFR signaling through dephosphorylation of tyrosine residues
What does the activation of EGFR lead to?
Internalization of the receptor and trafficking to the early endosomal compartment of the cell
What are the three independent sources that determine EGFR activation?
- Ligand-binding-driven EC dimerization
- Proximity-driven dimerization by clustering on a limited number of lipid rafts
- Direct asymmetric KD dimer formation with enhanced affinity
What is the most commonly expressed/overexpressed membranous oncogenic protein in cancer?
EGFR
What is the function of ErbB2?
Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons.
What is a mutation in the EGFR gene a biomarker for?
Non-small cell lung cancer
What treatment do most lung cancers with activated EGFR respond to?
Gefitinib
Will lung cancer treatment improve?
Lung cancer death rates have fallen sharply in the US in recent years, while survival rates have improved. This is largely due to newer treatments, according to a study led by researchers from the US National Cancer Institute (NCI) and published recently in the New England Journal of Medicine
What is the frequency of EGFR gene amplification in gliblastomas?
Observed in approximately 40% of tumors
