Cancer 9: External factors controlling division Flashcards
What are the two types of external influences detected by cells?
- chemical
- physical
Give examples of chemical influences
hormones, growth factors, ion concs
Give examples of physical influences
mechanical stresses, temperature
What external factors INFLUENCE cell division?
- growth factors
- cell-cell adhesion
- cell-ECM adhesion
Why does cell spreading require energy?
-modulate cell adhesion and the cytoskeleton
How does cell-ECM adhesion influence cell proliferation?
-cells need to be bound to extracellular matrix to be fully competent for responding to soluble growth factors
What processes can occur ONLY when the cell is attached to ECM
- protein synthesis and proliferation
- attachment to ECM may be required for cell survival
What determines the cell phenotype and give examples
-the composition of the matrix
in interstitial matrix - mammary epithelium does not differentiate to secretory cells
in basal lamina matrix - mammary cells organise into organoids and produce milk proteins
How does the cell receive information about its surroundings from ECM adhesion?
- cells have receptors on their surface that bind specifically to ECM molecules
- these molecules are often linked at their cytoplasmic domains to the cytoskeleton
- this arrangement means that there is mechanical continuity between ECM and the cell interior
What is the structure of integrins?
- heterodimer complexes of alpha and beta subunits
- associate externally by their head regions
- the leg regions span the plasma membrane
-ligand binding occurs at the junction of the head region
How do most integrins link to the actin cytoskeleton?
-via actin-binding proteins
What do integrin clusters form?
- focal adhesions or hemidesmosomes
- these clusters are involved in signal transduction
-some integrins also bind to specific adhesion molecules on other cells
How is signalling via ECM receptors carried out?
they can transduce signals
ECM binding to an integrin complex can stimulate the complex to produce a signal inside the cell
OUTSIDE- IN INTEGRIN SIGNALLING
How can cell-ECM adhesions and signals be turned off and on?
-conformational changes of the integrin complex to adopt flexed and extended molecular confirmations
What does the mechanical force produced depend on?
- the force generated by the cytoskeleton
- the stiffness of the ECM
-focal adhesions sense the mechanical properties of their surroundings
What to integrins recruit and to do what?
-cytoplasmic proteins which promote both signalling and actin assembly
What is INSIDE-OUT integrin signalling?
-a signal generated inside the cell can act on an integrin complex to alter the affinity of an integrin
Give an example of inside-out integrin signalling
-inflammation or blood clotting, switching on adhesion of circulating leukocytes
What is the position of the integrin for low-affinity and high-affinity?
low affinity: bent confirmation, weak or no binding to ligand
high affinity: extended confirmation, strong binding to ligand
What happens to the structure of the integrin when ECM binds to it?
- it causes further opening of the legs which exposes the binding sites for the recruitment of cytoplasmic signalling molecules
What do cells compete for at high density?
growth factors
What are the steps of the ERK MAP kinase cascade?
growth factor binds to receptor and activates ras - raf-MEK-ERK
-this leads to gene expression and proliferation
Why is proliferation dependant on anchorage?
- growth factor receptors and integrin signalling complexes activate identical signalling pathways but are weak individually
- however together activation is strong and sustained
What is the difference between cell junctions of short and long term contact interactions?
SHORT TERM: do not form stable cell-cell junctions
LONG TERM: formation of cell-cell junctions
