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Slide 1
Signalling & Cell Division

Module 6: Signals Dictate Cellular Decisions

Dr James Tsatsaronis

Department of Biochemistry and Genetics Slide 2

Intended Learning Outcomes
(ILOs)
After this lesson students will be able to:
• Describe the structure and activation steps of receptor
tyrosine kinases (RTKs)
• Outline how RTK and MAPK signalling cascades induce
cell division and survival
• Explain how mutations in EGFR and other MAPK
components can lead to cancers

Slide 3
 Receptor Tyrosine Kinases (RTKs)
• RTKs: Plasma membrane
receptors with intrinsic protein
kinase (add phosphates) activity
• Extracellular ligand binding
domain and intracellular tyrosine
kinase
• Upon ligand binding a single
receptor chain, the receptor
dimerises
• Receptor auto-phosphorylates
and activates tyrosine kinase
activity
• Receptors for insulin (INSR) and
many growth factors are RTKs

Slide 4
 Kinase cascade
• RTK activation triggers
downstream signalling
through RTK target proteins
and activates signalling
cascades
• At each step, the signal is
amplified through kinase
activity
• Families of kinases involved
in responses to growth
factors (mitogens) are part of
the MAPK family
• Mitogen activated protein
kinase

Slide 5
MAPK cascades

• Four major MAPK

protein kinase
cascades
• ERK pathway activated
by growth factors
• JNK, p38 and ERK5
activated by
environmental stress
(e.g. osmotic shock,
ionisation radiation)

Roberts and Der (2007)

Slide 6
 Mutations in signalling pathways can
promote uncontrolled cell division
• Mutations in RTK and MAPK
genes can switch kinases
permanently “on”
• Normal receptors for
epidermal growth factor (EGF)
respond to EGF to activate
receptor kinase activity
• ErbB2 (Her2) lacks the ligand
binding domain & is locked in
the active conformation
• Sends constant “divide”
signals regardless of the
presence of EGF
Slide 7
 Ras-MAPK pathway

• EGFR, Ras and Raf are

mutationally activated/
overexpressed in many
cancers

Roberts and Der (2007) Slide 8

Serial mutations in MAPK & other
genes can lead to cancer

Slide 9
 Protein kinases are cancer
therapy targets

• Prompted development of specific

kinase inhibitors as cancer therapies:
• Imatinib (Gleevac)
• Erlotinib (Tarceva)
• Imatinib is a specific tyrosine kinase
inhibitor, occupies the TK active site
in some enzymes
• Other drugs target RTKs through
other mechanisms
• Trastuzumab (Herceptin)
• Used in many leukemias and other
cancer types
Slide 10
Summary

• Receptor tyrosine kinases (RTKs) bind ligands, including

growth factors (mitogens) to induce signalling
• Mitogen activated protein kinase (MAPK) signalling
downstream of RTKs induce cell proliferation and survival
through a cascade of protein phosphorylation events
• Mutations in RTK and MAPK genes can induce
inappropriate cell division and survival signals leading to
cancer
• Inhibition of kinase activation or blockade of RTK signalling
represent viable cancer treatment avenues

Slide 11
Resources

• Lehninger Principles of Biochemistry Seventh

Edition (2017), W. H. Freeman and Company
• Chapter 12.4 and 12.11

• Molecular Biology of the Cell Sixth Edition (2015),

Garland Science
• Chapter 15

Slide 12