Oncogenes and signalling pathway 2

• Proto-oncogenes


  Genes that can become cancer-causing oncogenes when mutated
• Ras


  A protein that plays a central role in signal transduction and can become activated in cancer
• Signalling pathways

  • Integrin
  • VEGRF2
  • TGF beta
  • Wnt
  • GPCR
  • Hedgehod (nonconventional)
  • Notch (nonconventional)
• Integrins

  • They physically link cells to the extracellular matrix
  • They inform cells if tethering to ECM components has been achieved
  • They facilitate motility by making or breaking contacts with the ECM
• Integrin structure

  Contains alpha and beta subunits
• Integrin signalling pathway


  ECM-integrins-Sos-Ras-Erk
• Inside-out signalling

  Signals from inside the cell are communicated to the extracellular integrin domains, causing conformational changes that regulate integrin affinity for extracellular ligands
• Outside-in signalling

  Integrins provide information on the location and local environment of the cells, their adhesive state and surrounding matrix, leading to cellular responses like migration, survival, differentiation, motility
• Key molecules in integrin signalling

  • Focal adhesion kinase
  • Src-family kinases
  • Integrin-linked kinase
  • Adhesion adaptor proteins (e.g. paxillin, vinculin)
  • Rac
• Focal adhesions help the cell move by attaching to the ECM at the front, then detaching at the back as the cell rolls forward
• ADAMs

  Multidomain, multifunctional proteins that interact with integrins and control cell adhesion and motility
• ECM remodelling by integrins

  1. Integrin-mediated activation of metalloproteinases or plasmin to degrade ECM components

  2. Allowing cell movement and invasion
• Cilengitide

  An alpha-v-beta-3 integrin inhibitor used as an anticancer drug
• Cilengitide trials showed it did not improve outcomes when added to standard glioblastoma treatment, so it will not be further developed as an anticancer drug
• Neutralizing the beta-3 integrin can increase immunosuppression in cancer, which is undesirable as immunosuppressed people get more cancers
• Inhibiting alpha-v-beta-3 integrin

  Reduces VEGFR2 recycling, leading to its degradation and less angiogenic signalling
• ed ppl get more cancers than non immunosuppresed
• Role of different integrins

  • Inhibiting and causing cancer
  • Role of adding cilgentidide
• ARF6

  Regulates the functions of membrane traffic and actin remodeling
• VGFR2

  The angiogenic receptor. More of it = More angiogenic signalling
• VGFR2 internalisation and recycling

  1. When VGFR2 is not needed it can be internalised

  2. It then Neutralised into RAB 4 early endosome

  3. Leads to recycling back fo VGFR2 back to surface
• Role of Alpha V Beta 3 integrin

  Inhibits the recycling so the VGFR2 is degraded instead of recycled back to the surface
• Role of cilgentidide

  Neutralises AVB3 integrin so VGFR2 is recycled and continue proangiogenic signalling
• AvB3 and A5B1 integrin

  Work against each other
• A5B1 and EGFRr internalisation and recycling

  1. A5B1 and EGFRr internalise together into early endosome

  2. Then coupled with RCP protein allowing it recycled back to the surface, and dissociate

  3. EGFR is free to continue oncogenic signalling
• Role of AVB3 integrin

  Counteracts recycling by inhibiting RCP protein
• Role of cilegentitide

  Inhibits AVB3, so recycling occurs, = continuation of oncogenic signalling
• VEGFR2 structure and receptor signalling complexes

  • Can homo/hetero dimerise with other VEGFRs
  • Can heterodimerise with other family of receptors
  • Can form complexes with a number of other proteins
  • Multidomain transmembrane
  • Extracellular: VEGF binding domain
  • Intercellular: contain 2 tyrosine kinase domains 1 and 2 and the C terminus
• VEGFR signalling

  This signalling is bad in cancer as causes blood vessel permeability
• VEGFR signalling pathway

  1. Src-FAk-paxillin cascade that regulates focal adhesion turnover leading to blood vessel permeability

  2. Src can also communicate to VE-cadherin to internalise it

  3. Internalisation causes VE-cadherin degradation that causes opening of the paracellular junctions of the endothelial cells causing permeability of blood vessels

  4. Permeable blood vessels let cancer cells in to allow its spread to distant site

  5. Cancer blood vessels are leaky allowing passage of molecules so cadherin is downregulated in cancer
• TGF-beta pathway

  • Can be good or bad as it can act as a tumour suppressor in the early stages but can also act as a tumour promotor
• TGF-beta signalling pathway

  1. Ligand binds to the type 2 TGF beta receptor

  2. Forms a tetromer

  3. Phosphorylated of the kinase domain

  4. Smad 2/3 recruited that is phosphorylated by the receptor

  5. Smad 2/3 binds to smad4(regulatory smad)

  6. This complex translocates to nucleus and activate target genes that cause tumour suppression or tumour promotion
• Immunostaining for SMAD4 (in brown) in pancreatic intraepithelial neoplasias


  • Top: lots of brown staining
  • Cancer: bottom staining is lost
• Diff TFGbeta ligands

  • BMP
  • Activin
  • TGFbeta
• TGF-b signalling

  Has a dual effect on tumour growth: double edge sword
• TGF-beta as a tumour suppressor

  • Induction of apoptosis & cell cycle arrest
  • Upregulation of CDK inhibitors p15 and p21
  • Downregulation of c-myc, a TF
• TGF-beta as a tumour promoter

  • Major regulator of the tumour microenvironment
  • Converts fibroblasts into myofibroblasts (more motile)
  • Upregulates MMP expression and plasmin generation by tumour cells
  • Stimulates invasion and metastasis
  • Overexpression of EMT promoters eg. snail, slug
• Cadherin

  • Most importance epithelial cell adhesion proteins
  • Cadherin from one cell binds to the cadherin on the other cell keeping the 2 epithelial cells together = tight binding
• Structure of cadherin

  • Cytoplasmic domain can bind to p120, Beta catenin and alpha catenin
  • Alpha catenin binds to actin
  • Maintains cell shape
  • Actin maintain cell strength and shape and cell motility when necessary
• Wnt proteins

  • 19 highly conserved secreted glycoproteins
  • Frizzled: family of 10 seven transmembrane domain cell surface receptors, can form homo- and heterodimers
  • Co-receptors: low density liprotein receptor-related protein 5 (LRP5) or LRP6
  • Other receptors that bind wnt proteins: ROR2, RYK etc..