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SIGNALLING PATWHAYS FROM THE MEMBRANE TO THE NUCLEUS
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Mis-regulation can lead to a
host of diseases
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After a signal binds to its receptor, the ligand-receptor complex can move into the
nucleus where it can cause a transcriptional change, or it can remain in the
cytoplasm and cause a signalling cascade
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Cells make different decisions depending on the input
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These ‘decisions’ are the phenotypic behavioural outputs, such as cell death,
differentiation, proliferation or cell survival
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The extracellular signals come from a variety of sources:
§ Cell:cell contact such as ICAMs and cadherins
§ Cell:cell matrix contact, such as integrins
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There are four types of “classical”
receptors:
§ GPCRs
§ Ion-channel receptors
§ Tyrosine Kinase-linked receptors
§ Receptor tyrosine kinases
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These receptors are ‘activated’ via ligand binding events that trigger signalling
cascades
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Each phosphorylation event may have different effects on protein activity: increase
or decrease
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The kinase can phosphorylate on more than on residue, where one can be a
suppressor and the other can act as an activator once phosphorylated
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Kinases are capable of phosphorylated:
§ Y – tyrosine
§ T – threonine
§ S – serine
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Mitogen Activated Protein Kinases (MAPK):
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EGF Binding to the EGFR – Erk nuclear events:
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Grb2 contains two SH3 groups and one SH2 group
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Its SH3 domains have an affinity for two distinct proline-rich sequences
present in Sos, while its SH2 sequence associated with a phosphotyrosine
present on the C-terminus of the ligand-bound receptor, EGFR
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Consequently, Sos, which seems usually to float freely in the cytoplasm, now
becomes tethered via the Grb2 linker to the receptor
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à GAPs – GTPase activating proteins

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It consists of:
§ RAS binding domain
§ Serine/threonine kinase domain

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Ras can dimerise Braf/C-raf and are most often found isolated
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Raf is folded and inactive in the cytoplasm, bound to 14-3-3 – recognises
phosphorylated serine residues and binds to them, thus locking the protein
and blocking the RAS domain from binding to any of its substrates
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GTP-bound Ras attracts and bind Raf via its effecter loop, thus tethering Raf
to the plasma membrane via Ras
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14-3-3 is lost from the RAS binding domain – dephosphorylation of the Raf
dimer forms
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Raf is then phosphorylated at additional residues thus activating its kinase
domain
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Activated Raf then phosphorylates MEK (a MAPKK); MEK is actually a “dualspecificity kinase”, which means that it can phosphorylate serine/threonine
residues as well as tyrosine residues
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MEK uses these powers to phosphorylate two other kinases, the extracellular
signal-regulated kinases 1 and 2, commonly referred to as Erk1 and Erk2
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Once phosphorylated, each of these Erks then phosphorylates substrates
that, in turn, regulate various cellular processes including transcription, such
as the cyclin D1 gene
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This signalling pathway had a cyclic feedback regulation system that includes
phosphatases that negatively feedback into the pathway, and stop the
signalling cascade
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Such as the negative feedback from Erk1 and 2 onto Sos
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à Raf is only active when it is tethered to the plasma membrane
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Integrins are also required for ERK induced cyclin D1 regulation
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This is because the activation of Erk using the growth factor alone is
not strong enough to cause increased transcription of cyclin D1
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There are 3 isoformrs of JNK - a,b and g
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JNK is a serine/threonine kinase that is phosphorylated on its threonine and tyrosine
residues
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JNK induces two genes encoding the Fos and Jun TFs
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Pancreatic cancer has somatic mutations of Jnk and Atf2 in pancreatic cancer cell
lines
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As you can see, several retroviral oncogenes are derived from genes for nuclear
transcription factors, such as fos, jun, myc etc

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