Cell Signalling in Cancer Flashcards
What is cell signalling?
The interchange of information between a cell and its environment
Why is cell signalling important and how does it relate to cancer?
Cells must be able to give an appropriate response to a signal, and different pathways involved include growth, proliferation, survival. Mutations in the pathways can lead to cancer via evasion of apoptosis, uncontrolled growth, etc.
What are RTKs?
Receptor Tyrosine Kinases, of which humans have 20 subfamilies. The cytoplasmic tails act as docking sites for specific intracellular proteins. SH2 regions on proteins bind to phosphorylated residues on RTK tails.
Describe the EGFR (ErbB-1) RTK family
A family of 4 highly related receptors: EGFR, HER2 (ErbB-2), HER3 (ErbB-3), HDER4 (ErbB-4). Activated by epidermal GF family, and they have disulphide bonds determining binding specificity. They have different structural motifs such as Ig-like domains, heparin binding sites, glycosylation sites. They bind to eachother in different concs. HER2 doesn’t bind ligands - is a coreceptor. EGFRs found in many organs, abnormal expression/activation is associated with many different cancers
Describe how RTKs function
The binding of a ligand to RTK causes dimerisation of the RTK, which causes cross phosphorylation of the tyrosine residues. This leads to the recruitment of proteins which bind via SH2 domains (can be multiple proteins). Some proteins bind directly, others by adaptor proteins which bind other proteins via SH3 domains. This then carries on towards the nucleus, where it affects transcription. Crosstalk occurs by different pathways activated by the same RTK, evoking the same response.
Explain how Ras protein is activated by RTK signalling
RTK is activated by a ligand, and it’s cytoplasmic tail is phosphorylated. This results in the binding of Grb2 via its SH2 domain to the phosphorylated residue. Sos binds Grb2 via its SH3 domain, and acts as a nucleotide exchange factor which switches GDP for GTP, activating Ras
Explain the MAPK signalling pathway
It is one of the most common signalling pathways, very relevant to cancer. RTK activates Ras, which activates Raf (MAP kinase kinase kinase), which phosphorylates MEK (MAPKK), which phosphorylates ERK1/2 (MAPK) which phosphorylates TFs. Each kinase acts on several factors, amplifying the signal. Many GFs singal via this pathway
Explain the PI3K signalling pathway
Phosphoinositide-3-kinase is activated by Ras binding to its Ras binding domain or by directly binding of RTKs such as PDGFRB via their PI3K docking site. This stimulates the catalytic domain of PI3K which phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to 3,4,5-triphosphate (PIP3) - these are both phospholipids residing in the membrane. PIP3 production results in activation of downstream pathways controlling cellular functions critical to cancer by binding to proteins with a pleckstrin homology (PH) domain (signalling/cytoskeletal proteins) like PDK1 and AKT (PKB). PIP3 brings them to the membrane, and PDK1 phosphorylates AKT, which inhibits pro-apoptotic BAD and BAX, leading to cell survival. Phosphatase and tensin homologue (PTEN) inhibits this pathway by dephosphorylation of PIP3 - inactivations of PTEN are in 30-40% of cancers. AKT also phosphorylates several other proteins leading to survival, growth, prolif.
What type of receptor are GPCRs and give some examples of ligands
GPCRs are cell surface receptors and their ligands are catecholamines such as adrenaline and dopamine
Give examples of some ligands for intracellular receptors
Glucocorticoids, androgens, oestrogen, vitamin D, thyroid hormone
What type of receptor are RTKs and what are some examples of their ligands?
Cell surface receptors and EGF, Insulin, VEGF
What type of receptor are receptors with associated kinases?
Cell surface receptors and growth hormones, IL-1 receptor associated kinase
What type of receptor are receptor protein serine/threonine kinases and give some examples of their ligands
Cell surface receptor and TGF-B (cytokine), Bone morphogenic protein (BMP)
What type of receptor are other enzyme linked receptors and give some examples of their ligands
Cell surface receptors and atrial natriuretic peptide (ANP), Uroguanylin
Name some ligands of ligand gated ion channels
Acetylcholine, glutamate
