Growth Factors, Receptors, And Cancer - Quiz 3 Flashcards
Intercellular comunication
- Critical to embryonic development, tissue differentiation, and systemic responses to wounds and infections.
These are initiated by Growth Factors
Growth Factors
- Secreted protein that is able to stimulate the growth and/or proliferation of a cell by binding to a specific cell-surface receptor displayed by that cell.
Mitogen
An agent that provokes cell proliferation
Secretome
- The collection of proteins that are released by a cell into the extracellular space under specific physiological conditions or states or differentiation, often focused on signaling proteins
Scratch/wound healing assay
- A scratch wound healing assay is used to measure basic cell migration parameters. A “wound” is created in a cell mono layer by scratching with a pipette tip. Cell migration into the wound space is measured.
Platelet-derived growth factor (PDGF)
- A potent mitogen for mesenchymal cell types
- Produced and released by platelets (and other cell types) upon activation
- Five different isoforms of PDGF
Platelet-derived growth factor receptor (PDGFR)
- Cell surface receptor for PDGFs
- Receptor tyrosine kinase (RTK)
- Two types of PDGFRs
What happens if PDFG or serum is not present?
Cells are not able to proliferate
What is cancer?
It is a disease of aberrant signal processing.
Steps of signal transduction
- Receptor
- Transduction
- Response
- Signal Termination
Molecules that are involved in cell communication
-
Signaling molecules
- Ligands
- Receptor (e.g., RTK)
- Adaptor proteins (e.g., Grb2)
-
Relay/signal processing molecules
- SOS, Ras, Raf, MEK, ERK
- Scaffolding proteins - Response/ output
- activation of transcription factors
Kinase
- An enzyme that removes the y phosphate from ATP and covalently attaches the phosphate moiety to substrate molecules, often but not exclusively to proteins.
What side chains of amino acid residues do protein kinases attach phosphates?
- Serine/threonine kinases
- Tyrosine kinases
- Receptor tyrosine kinase
- Non-receptor tyrosine kinase
What is SRC
- non-receptor tyrosine
- phosphoprotein
- can phosphorylate more than 50 distinct substrates
Phosphoprotein
a protein to which one or more phosphate groups have been covalently attached
Interactome
a set of protein-protein interactions
Receptors for growth factors are enzyme-linked, transmembrane receptors
- Receptor tyrosine kinase (RTKs)
- TGF - beta (serine-threonine kinases)
- JAK-STAT (Janus kinase)
GF receptor domains
- Ectoderm (extracellular domain): ligand binding
- Transmembrane domain
- Juxtamembrane domain
- Cytoplasmic domain
Juxtamembrane domain
- Mutations in this domain are a common mechanism by which RTKs become constitutively activated and drive cancer progression.
Signaling through RTKs
- Receptor dimerization, ligand binding, and transphosphorylation
- RTKs can exist as monomers in an inactive state or as inactive predimers or larger scale clustering
Alterations/ mutations that result in deregulation of receptors
- Mutations affecting structure
- Overexpression
- Creation of autocrine signaling loop
- Gene fusions
Mutations affecting structure include …
- truncation of ectodomain
- can emit mitogenic signals constitutively - point mutation (amino acid substitutions)
Creation of an autocrine signaling loop
- In many types of cancer, tumor cells acquire the ability to make a growth factor for a receptor that they naturally display
Gene fusion causing constitutively dimerized receptors
- Ros is an RTK
- Fig is a protein that dimerizes spontaneously
- In glioblastoma, the reading frame of the ROS ectodomain is fused to the FIG reading frame
- The Ros-Fig fusion protein dimerizes resulting in constitutive, GF-independant dimerization and signaling.
JAK/STAT signaling pathway
- Janus kinase/signal transducer and activator of transcription
- pathway activated by cytokines, interferon, and some hormones
- Canonical signaling and. non-canonical deviations
JAKs are:
- Non-receptor tyrosine kinases
- noncovalently associated with cytokine receptors
Canonical Jak/STAT signaling
- Cytokines bind to the receptors bringing JAKs into proximity
- JAKs transphosphorylate and phosphorylate the C-terminal tails of the receptor creating a docking site for STAT monomers
- STATs are phosphorylated, then they dimerize, translocate to the nucleus, bind to DNA, and induce expression of target genes
TGF-β receptors
- Transforming growth factor-β (TGF-β) type I and type II receptors
● Serine-threonine kinases
Wnt/β-cateninsignalingpathway
● No Wnt signal: a complex of AXIN and APC allows GSK-3β to phosphorylate β-catenin.
This marks β-catenin for degradation by ubiquitin-dependent proteolysis.
● Wnt signal: Wnt ligand binds to the Frizzled receptors and the LRP co-receptor. Dishevelled is recruited by the receptor and prevents the destruction β-catenin
