Cell signalling

Course reviews

• 
  Kevin McCarthy 10 February 2026 9:08PM

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  As a non-biochemist the fact that the topic was introduced at a level that I could build upon throughout the rest of the course was greatly appreciated. Admittedly, I still needed to attempt the course twice, ceasing the first attempt two thirds the way through in section 3, only returning months later when the web site stated that the course completion was pending.
  
  The reliance on relatively dated texts has led to occasional inaccuracies as the subject matter has progressed over time (please see later for one obvious example, regarding the number of small G proteins; also, the statement ‘in a poorly understood mechanism‘ with regard to the MAP kinase pathway).
  
  The presence of a glossary would have been useful; that said, the opportunity for readers to create their own actually ensured greater insight than would otherwise been achieved from simply skimming over a pre-written one.
  
  With regard to most of the figures, it would have been greatly appreciated if higher resolution versions had existed for a surprising number of figures, e.g., for 1.2 Figure 3, 1.8 Figure 16, 2.2 Figure 18, 19, 20 and so on. The primary issue was not so much with the graphics themselves, but with the contained text that become even more blurred upon enlargement.
  
  Personally, I was intrigued with the ‘best/well-studied’ type statements, indicating the number of specifics within cell signalling that still remain unknown. Whether this is due to the presence of non-linear signalling path; extreme molecular diversity; spatial and temporal complexity; stochasticity; experimental tools having perturbed the system; emergent behaviour; evolutionary bricolage or even a basic lack of a unified theoretical framework in the first place!
  
  Miscellany:
  2.2 “propanolol acts as an antagonist of β receptors”  propranolol
  
  2.3.2 “7TM proteins have been classified into FOUR [rather than THREE] classes, A, B, C”
  
  2.3.2 effect -> affect
  
  2.3.3 immunoglUbulin-like -> immunoglObulin-like
  
  2.3.4 kinaseassociated -> kinase-associated as used later in the sub-section
  
  3.2 The intrinsic GTPase activity of the a subunit -> α subunit
  
  3.5 “more than 70 other small G proteins”, this number came from the 1990s to early 2000s. Genome sequencing has since expanded placing the Ras superfamily at over 150 members.
  
  3.6.1 the statement “in a poorly understood mechanism” with regard to the MAP kinase pathway is no longer appropriate. It would now be more appropriate to consider that the ‘full mechanism is still not completely nailed down’, because Raf activation is surprisingly intricate. Since structural biology, single molecule imaging, and membrane biophysics have filled in most of the gaps.
  
  3.6.1 “e xtracellular signal r egulated k inase” …this may have been attempting to emphasise the derivation of ERK, but looks more like a typographical error? For example, within Box 4 of 3.6.2 the author simply underlines the respective letters.
  
  3.6.1 Box 3 “PERMANENTLY switch on the downstream pathway”, surely this should be “persistent” rather than “permanent” in the literal sense, since cells can still: degrade the mutant protein; dilute it through cell division; counteract it with phosphatases or feedback inhibitors; undergo apoptosis if signalling becomes toxic; silence the expression construct over time?
  
  3.6.2 “The JAK–STAT pathway has RECENTLY become the basis for the development of techniques for the study of protein–protein interactions” …”recently” would surely have applied up until more than a decade ago? Indeed, it has been overshadowed by more modern systems (e.g., optogenetics, chemically induced dimerisers, split protein systems, proximity labelling, BioID, TurboID, APEX2, NanoBiT…) Surely, at the very least: “The JAK–STAT pathway has long been used as a framework for engineering inducible protein–protein interaction systems.”?
  
  3.7 “inositolphospholipid” -> “inositol phospholipid”?
  
  3.7 “approximately 20 minutes after cell stimulation” -> the “20 minutes” is surely based in dated research since there is no single canonical timepoint? MKP‑1 induction timing varies dramatically depending on all of the following: cell type; stimulus (EGF, NGF, cytokines, stress, serum); MAPK isoform (ERK, p38, JNK); chromatin accessibility; feedback strength; mRNA stability. Indeed, in modern datasets (RNA‑seq, single‑cell time courses), MKP‑1 induction can occur anywhere from: 5 minutes (strong ERK pulses in epithelial cells); 15–30 minutes (classic fibroblast serum response); 60+ minutes (stress‑induced p38‑driven transcription). Perhaps the following would thus be more appropriate: “MKP 1 is a rapidly induced immediate early gene whose expression typically rises within minutes of MAPK activation, though the exact timing depends on cell type and stimulus.”?
  
  4.1 Figure 47 shows a mechanistic/signalling view, showing the intracellular signalling cascade that explains how insulin activates glycogen synthase. I came across a graphic on ‘Slideshare’ that distributed these pathways across the specific cells (liver, muscle, pancreas and adrenal gland); perhaps the inclusion of such a systems physiological model might also be useful as a precursor (showing the direction of flux, rather than the molecular mechanism)?
  
  4.1 “In skeletal muscle, glucose enters the glycolytic pathway to produce ATP, the fuel for muscle contraction”. Presumably the coproduction of NADH has not been stated for the purposes of simplification? Otherwise, would a more complete description become: “In skeletal muscle, glucose enters the glycolytic pathway, generating ATP for contraction and reducing equivalents in the form of NADH. Under aerobic conditions this NADH is oxidised in mitochondria to support further ATP production, while during intense activity it is re-oxidised via lactate formation to sustain glycolytic flux.”?
  
  4.1 I must admit to finding the text block “Adrenalin has many effects… …(d) Glycogen synthase, which on phosphorylation is inactivated.” somewhat confusing. Given that this is mixing receptor signalling, kinase cascades, phosphatase regulation, neural input and three different PKA targets. My understanding is that it is explaining:
  “In skeletal muscle, adrenaline binds to β adrenergic receptors, activating Gαs and stimulating adenylyl cyclase, which raises cAMP and activates PKA. PKA rapidly promotes glycogen breakdown by phosphorylating and activating phosphorylase kinase, which then activates glycogen phosphorylase to release glucose 1 phosphate from glycogen. This glucose 1 phosphate enters glycolysis, generating ATP (and NADH) to support muscle contraction, with its end products handled according to oxygen availability. Motor neuron activity reinforces this process: acetylcholine triggers Ca²⁺ release, and Ca²⁺/calmodulin also activates phosphorylase kinase.
  At the same time, PKA prevents glycogen synthesis. It phosphorylates and inhibits PP1, the phosphatase that normally reverses the phosphorylation of phosphorylase kinase, phosphorylase, and glycogen synthase. PKA also phosphorylates and activates the PP1 inhibitor protein (Inhibitor 1), further suppressing PP1. Finally, PKA directly phosphorylates glycogen synthase, converting it to its inactive form. Together, these mechanisms ensure that glycogen breakdown is strongly favoured while glycogen synthesis is suppressed.”
  
  4.1 “phophorylase kinase” -> “phosphorylase kinase”
  
  4.2 2 “Three pathways converge in the regulation of glycogen synthase…” surely “ISPK/PP1G is not a “pathway” but a phosphatase complex activated by insulin.” ?
  
  4.2 4 “Three pathways converge in the activation of phosphorylase-by-phosphorylase kinase …” would a clearer version be: “Phosphorylase kinase is activated by Ca²⁺ and by PKA and inactivated by PP1.”?
  
  4.2 5 “Acetylcholine, adrenalin and glucagon promote glycogen breakdown, whereas insulin inhibits it.” Yes, but should tissue specificity be mentioned, e.g., “Acetylcholine (skeletal muscle), adrenalin (both muscle and liver) and glucagon (liver only) promote glycogen breakdown, whereas insulin inhibits it.”?
  
  
  References
  
  There are at least three references to relatively old editions of texts, which may have led to issues such as the number of small G proteins, e.g.:
  
  “Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2002) Molecular Biology of the Cell (4th edn), Garland Science, New York.” , which is currently in its 9th edition.
  
  “Gomperts, B. D., Tatham, P. E. R. and Kramer, I. M. (2002) Signal Transduction, Academic Press, London.”, which is currently in its 3rd revised edition (2015) under the sole authorship of Kramer, I. M.
  
  “Stryer, L. (1995). Biochemistry (4th edn), W.H. Freeman and Company, New York.”, which is currently in its 7th edition.

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• 
  John McDonald 1 April 2025 5:21PM

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  A very detailed course. I've studied a number of the OpenLearn Sciences Courses and this is indeed an Advanced Course, probably at 3rd year degree level. There is much more detail than one could readily retain unless making a very serious attempt to understand and memorise. I would however have liked the course to bring in the concepts of targeted cancer and immunotherapies that are aimed at interfering with many of these signalling pathways and their targets. That would demonstrate how science has leveraged this knowledge to develop targeted therapeutics.

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