CELLULAR FUNCTION

which concept is cell signalling akin to 

induced fit (rather than lock and key) 

state the types of cell communication

• contact-dependent/ juxtacrine: signalling cell and target cell are in contact

• paracrine: signalling cell and target cell are in proximity

• endocrine: signalling cell and target cell are distant (signal arrives through the bloodstream)

• synaptic: depends on neurotransmitter 

give an example of cell signalling in dentistry

• osteointegration dependent on autocrine PDGF signalling

diagram showing summary of steps of communication

give an example of a process in the order of the steps of communication

list the types of signals (6)

• growth factors

• hormones

• vitamins

• chemicals

• enzymes

• sugars

give examples of the types of signals and their response

give examples of physiological cell responses

• growth i.e. cell division

• differentiation

• migration

• metabolism

• cell survival

what is considered a pathological response

when a cell produces a signal that is not needed

give examples of pathological cell responses

• apoptosis

• gene transcription

• secretion

• contract/ relax

give a specific example of a physiological vs pathological response

physiological

• macrophages produce and secrete VEGF during wound healing to induce angiogenesis

pathological

• cancer cells produce and secrete VEGF to stimulate greater blood supply 

• this allows the tumour to grow more 

what does this image show about receptor specificity

• acetylcholine can bind to many different receptors

• so even though it is one chemical, it can induce different responses based on the receptor it binds to

state the types of receptors 

• intracellular receptors

• membrane receptors 

  • ion channel-linked receptors

  • G-protein-linked (7-TM) receptors

  • enzyme-linked receptors

  • receptor tyrosine kinases (RTKs)

outline intracellular receptors

• aka internal receptors or cytoplasmic receptors

• signal is hydrophobic therefore it can pass through the cell membrane

• signal is transported into the nucleus to provide signal transduction e.g. induce transcription

give examples of intracellular receptors

• steroids

• nitric oxide

outline membrane receptors

• cell surface, membrane-anchored or integral proteins that bind to external ligand molecules

• convert an extracellular signal » intracellular signal

• ligands that interact with cell-surface receptors do not have to enter the cell

what are the three main components of membrane receptors

• external ligand-binding domain (extracellular domain)

• hydrophobic membrane-spanning region

• intracellular domain

outline ion channel receptors (membrane receptor) 

• interaction of a chemical with the receptor causes opening or closing i.e. a conformational change

• very fast (so involved in rapid cell signalling)

• e.g. rapid synaptic signalling between nerve cells and other electrically excitable target cells

outline G-protein-linked (7-TM) receptors (membrane receptors) 

• indirect mechanism

• trimeric GTP-binding-protein (G protein) mediates the interaction between an activated receptor and a separate target plasma-membrane-bound target protein

  • receptor is an inactive molecule, needs to bind to G-protein to become active

• very common in mechanisms across the body e.g. acetylcholine in pacemaker cells and salivary glands

outline enzyme-linked receptors (membrane receptors)

• usually single-pass transmembrane proteins that have their ligand-binding site outside the cell

• hydrophobic single alpha helix transmembrane domain

• catalytic or enzyme-binding site inside

• majority are receptor tyrosine kinases

—

diagram: single pass transmembrane protein dimerises therefore depicted as a pair

outline receptor tyrosine kinases (RTKs) - class of enzyme-linked receptors

• cell surface receptors for growth factors e.g. EGF, VEGF, cytokines and hormones

• have intrinsic enzyme activity - dimerises and autophosphorylates upon ligand binding to the extracellular domain, activating the receptor

• conformational change allows signalling molecules to bind and initiate downstream cascades

• key regulators of normal cellular processes - also have critical roles in the development and progression of many cancers

diagram showing the complexity of signalling pathways

what do signalling pathways target

therapeutic targets 

• signalling pathways can also be used as therapeutic targets

what is a solution to cancer cells secreting VEGF to stimulate angiogenesis

• produce a signal for the VEGF receptor

• this cuts off the blood supply (nutrients) to the cancer cells which leads to cell death

diagram showing RTK hyperactivation and dysregulation in cancer

outline therapeutic targets (RTKs)

• RTKs have a central importance in ‘pro-growth’ signalling networks

• multiple cancers display ‘oncogenic addiction’ to RTKs

• RTKs therefore represent a major class for targeted therapeutics 

  • small molecule-based tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mABs)

  • TKI and mABs have been approved for numerous cancers

what are limitations of TKI and mABs

• off-target effects

• resistance

if a drug name ends in -nib what is the drug’s mechanism of action

the drug is an inhibitor

if a drug name ends in -mab what is the drug’s mechanism of action

the drug is a monoclonal antibody

table showing therapies for head and neck squamous cell carcinoma

give an example of a case study in cancer precision medicine

breast cancer

• routine to check for epidermal growth factor receptor 2 (HER2) overexpression on diagnosis

• overexpressed in 15-20% of cancers

what is HER2 treated with

either mABs

• Trastuzumab - Herceptin

• Pertuzumab - Perjeta

or TKIs (tyrosine kinase inhibitors)

• Lapatinib - Tykerb

• Neratinib - Nerlynx

what other receptor is it routine to check for in breast cancer diagnosis

oestrogen receptor 

• expressed in 75% of breast cancers

• oestrogen promotes growth 

what is oestrogen receptor expressed in breast cancer treated with

oestrogen mimic

• Tamoxifen - targets signals, not the tumour itself