The signal transduction pathway and receptors (Petronini) Flashcards
_____________ are able to stimulate cell proliferation
Growth factors ( some can be inhibitors)
What do ligands eventually activate during the signal transduction pathway ?
Transcription factors.
An unbalance between positive and negative regulators induces
abnormal cell signaling and promotes ________?
cancer
The homeostasis of the cell population in terms of the number of cells is regulated by two
different aspects:
- The rate of cell proliferation
- The rate of cell death
What are the receptors in the signalling transduction?
Tyrosine Kinase Receptors, JAK Kinase ( non Tyrosine kinase receptors) , GPCR ( spans the membrane 7 times), Hormone receptors ( for Vitamin D thyroid hormones)
EGFR (Epidermal Growth Factor Receptor), PDGF Receptor (Platelet Derived
Growth Factor), FGF Receptor (Fibroblast Growth Factor), VEGF receptor (Vascular
Endothelial Growth Factor), insulin receptor, and IGF-1 Receptor are all EXAMPLES of ___________?
Receptors with the transmembrane domain and rich in hydrophobic amino acids, and an intracellular
domain, that contains the tyrosine Kinase domain.
Activation of Tyrosine Kinase consists of ___ steps?
1) The binding of the GF
2) the dimerization of the monomeric receptor, for example, EGF Receptor.
3) the autophosphorylation of the receptors, due to the tyrosine kinase
domain.
Then the phosphorylated Tyrosine binds some proteins.
Phosphorylated tyrosine is like a
docking site for some proteins, that activate the most popular transduction pathway which is_________?
MAP Kinase Pathway, In this case, the phosphorylated tyrosine binds to the proteins called
GRB2 and SOS (SOS means son of sevenless).
whats MAP kinase?
Mitogen activating protein kinase
What is HER family?
Human epidermal growth factor receptor
HER2 (Human Epidermal Growth Factor 2) is a protein that regulates cell growth. It is a member of the epidermal growth factor family of tyrosine kinase receptors. HER2 amplification is a major driver of tumor development and progression in a subset of breast cancers
Why are HER receptors very important?
because some of them are cultured in cancer, for
example, EGFR, also called HR1 or ErbB-1, is mutated in 30% of lung cancer. In other
words, it is mutated in non-smoker subjects and for these people the target therapy inhibits
the autophosphorylation of the receptor, blocking the transduction pathway
Another receptor that is involved in cancer is HER2, also called ErbB-2. This receptor is
another expression of ________ cancer?
breast, HER2 is amplified and it’s overexpressed in the plasma
membrane.
For HER2 amplification there is a drug that is called _____________, which is an antibody that
binds to these receptors.
Trastuzumab
EGFR receptors, not only bind to EGF but also to?
TGFalpha (transforming growth factor
alpha).
Does HER2 have specific ligands?
No
HER3 & HER4 ligand is __________
Heregulin.
MAP-Kinase Pathway involves _______, ___________, and ____________, that at the
end are phosphorylated and move to the nucleus.
RAS, MAK kinase, transcription factors
what is mTOR?
The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration to maintain cellular homeostasis
what is Rapamycin?
Rapamycin and its derivatives are the inhibitors of the mTOR.
Tumors with a high level of phosphorus are tumors that?
survive to induced apoptosis, and
are intrinsically resistant to the therapy, so the prognosis of these tumors becomes worse.
What is STAT?
Signal Transductor Activator of Transcription, it is the
transcription factor, that activates by phosphorylation operated by JAK.
what does Adenylyl cyclase do?
Induces the formation of cyclic AMP from ATP, Cyclic AMP binds to the regulatory subunit
of PKA (Protein Kinase-A) and the catalytic subunit of PKA is activated and phosphorylates
the substrate.
Examples of intracellular receptors?
Vitamin D3 Receptor
Thyroid Hormone Receptor
Steroid Hormone Receptor
The steroid receptor activity is controlled by binding other proteins and one of these proteins is?
HSP90 Protein which binds to steroid hormone receptors.
What do Phospholipase C- Beta and Gamma break?
PIP2( (Phosphatidylinositol Bisphosphate )
and form IP3 (Inositol Trisphosphate) and DAG (Diacylglycerol)
IP3 can determine an increase in the free intracellular ________?
calcium, because it induces the
release of calcium from the endoplasmic reticulum, causing a flux from inside to outside
What does DAG activate?
PKC ( protein kinase C )
What is Bridging Protein (GRB2) and SOS role?
They activate the RAS by phosphorylating it GDP to GTP
Ras Proteins are activated when they bind GTP and will be active until
GTP is converted to GDP by ________.
GTPase
What is GTPase called?
GAP
Endogenous GTP activators are?
G proteins
Ras are dependent by?
GAP
_________are mutated in 30% of human tumor
RAS, when RAS is mutated it becomes insensitive to GAP
The mutation is related to the codon number?
12, it codifies for glycine, putting proline there RAS remains normal, but for any other amino acid it becomes mutated
RAS kinase activates the ________ ?
RAF kinase , which in turn activates MEK, MEK activates ERK and ERK activates the transcription factors.
RAF is mutated in ____________ and the drug for it is ___________, that inhibits Ras
melanoma, Vemurafenib
What are the RAS proteins?
- K Ras: Kristen Ras
- N Ras: neuroblastoma Ras
- H Ras: Harvey Ras
What is the most common tumor, in terms of mortality?
Lung tumor, in both sexes
AP-1 is composed by ____ and ____
Fos and Jun, AP-1 is one of the most important transcription factors
Stimulation of B-Raf (the kinase mutated in melanoma)
increases ______ and ______expression.
c-Fos and c-Jun expression
The most important transcription factor is called ?
MYC
PI3K ( considered as a proto-oncogene ) allows the phosphorylation of_____?
AKT, starting from PIP2 and PIP3
What is PI3K counteracted by?
PTEN ( a tumor supressor gene )
PI3K is a kinase and PTEN is a phosphatase
A very high number of pathways are affected by AKT. The most important pathway is related
to ?
Survival, When a cell has phosphoAkt elevated, these cells don’t die
_______ is a typical survival gene and _____ is a typical death gene.
bcl-2, bax
In 50-60% of human tumors, _____ is inactive or mutated.
p53
p53 is degraded when it binds to _______?
MDM2, that is a target of KT
______________ moves to the nucleus and binds p53 and p53 is degraded in the
proteasome.
phosphorylated MDM2
mTOR is activated by phosphorylation by ___________
G-protein Rheb
Rheb is maintained in the inactive state by the onco-suppressor complex consisting of the
______________
heterodimer TSC1-TSC2 (tuberous Sclerosis 1 and 2).
________ phosphorylates and then inactivates the TSC1/2 complex resulting in the activation of
mTOR.
AKT
_________ is a serine/threonine kinase that can exist in two multiprotein complexes
mTOR
what does mTOR2 do?
phosphorylation of AKT and
cytoskeletal organization.
_________ inhibits mTORC and it’s used to improve transplantation, for example, of kidneys
Rad001
It’s possible to prevent the rejection of an organ by inhibiting __________?
mTORC1, a lot of drugs that are immunosuppressive act on the mTORC1
What are cytokines?
polypeptides or proteins involved in inflammation, they regulate the most important pathways in immunology, And these receptors are not tyrosine kinase receptors,
but the transduction is mediated by JAK
JAK phosphorylates the tail of the receptor in the
intracellular compartment, phosphorylated tyrosine is the docking site for _______
STAT
if____________ is phosphorylated, it becomes a dimer and moves to the nucleus, activating
cytokine-responsive genes. So, the process consists in:
1. Binding to the cytokine.
2. JAK phosphorylates the receptor.
3. STAT binds to the phosphorylated tyrosine, becomes a dimer and moves to the
nucleus.
STAT
What is TGF beta?
a tumor suppressor by mediating its antiproliferative effects in a large variety of cell types.
EGF is produced by?
macrophages, and platelets in the epithelium
The most known mitogens of epithelial cells are___________________________
ERB B receptor family (EGFR-HER 2-
HER3-HER4).
what are PDGF?
30kDa dimers formed by 2 types of chains A and B (PDGF-AA, PDGF-BB, PDGF-AB).
It’s stored in the granules of the platelets is released after platelet activation, during the
repair.
It’s also produced by other cell types, such as activated macrophages, endothelial cells, and
smooth muscle cells. It’s able to induce migration and proliferation of fibroblasts, smooth
muscle cells, and monocytes. The receptors are PDGFR alpha and beta receptors
what are HEPATOCYTES GROWTH FACTOR (HGF)?
Also called scatter factor (SF). This factor induces the proliferation of hepatocytes in liver. The receptor of this growth factor is called MET, which is a tyrosine receptor. When MET is
mutated or overexpressed this tumor is very aggressive. MET receptor is involved during the
invasion and metastatic process, because it’s able to induce movement of cancer cells.
There are drugs that inhibit MET receptors
what is Vascular endothelial growth factor (VEGF)?
VEGF-A is the main angiogenetic factor and a very important aspect during tumor growth
because tumors don’t increase the mass until you have the production of new vessels, which
are important for nutrients and oxygen.
When a tumor is alimented by new vessels, they grow rapidly and become invasive, and can
give metastasis
all drugs with _______ at the end of the name are tyrosine kinase inhibitors, while when they
have _______ they’re monoclonal antibodies.
-inib, -umab
What is the signal that induces angiogenesis?
There is a sensor of oxygen in tumor cells, which is called HIF
what is EPO ( erythropoeitin) ?
it is a gene that is activated by HIF, Erythropoietin is a cytokine
very important in the production of red blood cells and erythropoietin gene is transcribed by
HIF.
what is FGF Fibroblast Growth Factor (a and b) ?
Important in repair processes (a) and angiogenesis (b). They are associated with ECM
heparan sulfate (inactive factor reservoir).
FGFR receptor is a tyrosine kinase.
What is Pleiotropic factor?
In some cell types (for example fibroblast) it is mitogenic, while in others (for example
epithelial cells) it exerts an inhibitory action on the growth and it inhibits the inflammation.
What is carcinoma?
Type of tumor that arises from the epithelial tissue of various organs,
Two ways stem cells divide are?
Symmetric: two identical stem cells
Assymetrci: one stem cell and one progenitor cell that is forever differentiated
Where totipotent cells are present?
Embryo and Blastocyst, they can produce all the components of an adult organism
Two types of stem cells in bone marrow?
- Hematopoietic stem cells give rise to platelets, erythrocytes, and leukocytes.
- Mesenchymal stem cells can produce different cells such as chondrocytes,
adipocytes, and muscle cells.
Where are multipotent stem cells are present?
- At the medullary level: hemopoietic stem cells
- In the intestine: intestinal crypt stem cells
- Stem cells in the epidermis
Pathways associated with stem cells are?
- WNT
- Notch
- RTK
- TGF beta
Explain the pathway of RAS/RAF/MEK/ERK
EGFR gets activated by TGF-a, EGF, betacellulin, epiregulin
EGFR will activate RAS by activating SOS and GRB2
1) RAS activates B-RAF ( B-RAF can also be activated by PAK, Src, HSP90 and 14-3-3)
2) B-RAF activates MEK1/2
3) MEK1/2 activates ERK
4) ERK Activates the TF such as c-fos, c-jun, MYC, Ets which are important in cell proliferation and survival
Explain the AKT signalling pathway
1) GPCR or RTK ( tyrosine receptor kinase) gets activated by growth factors, ex: insulin
2) PI3K gets recruited when one of these receptors gets activated
3) PI3K leads to an increase of PIP3 levels, which leads to the recruitment of PDK1
4) PDK1 directly phosphorylates the AKT at threonine to activate it OR it can recruit mTORC2 which phosphorylates the AKT at serine activating it
5) AKT inhibits AS160 to increase glycolysis; inhibits TSC1/2 to let Rheb activate mTORC1 which is important for protein synthesis and inhibition of autophagy; inhibits FOXO which inhibits cell Survival and proliferation, as a result, there is cell Survival and proliferation; inhibits GSK3 which inhibits GS ( glycogen synthase), as a result, there is more glycogen synthesis
AKT is turned off by PTEN which doesn’t let PDK1 be recruited or PHLPP can dephosphorylate AKT at serine, another way is by PP2A deposphorylates AKT at threonine
Explain the JAK/STAT pathway
There are gp130 and gp140 receptors
JAK states for Janus Kinase
The ligands are GM-CSF, Tins( Erythropoietin, prolactin, Thrombopoietin, leptin), Ters( Interleukins, interferons)
1) the receptors get activated by a ligand
2) once the receptors are activated, JAK phosphorylates itself
3) JAK activates the AKT pathway, and RAS pathway, but most importantly it activates the STAT
4) when STAT is phosphorylated it dimerizes and enters the nucleus, binds the GAS( gamma activating sequence elements), and induces cellular survival and proliferation.
Describe the Wnt/B-catenin Signaling Pathway
In an inactivated state B-catenin is bound and regulated by a large protein complex( Axin, CKI, GSK3, APC, Dvl, B TrCP) - it is known as the destruction complex
Ubiquitination of B-catenin leads to proteasomal degradation of it, lowering the B-catenin levels. This all happens when it is in an inactivated state.
In active state of B-catenin, Wnt binds to Frizzled receptor. When Frizzled is activated it leads to the phosphorylation of LRP. LRP leads to the translocation of the destruction complex near the Frizzled and LRP receptors. When Dvl binds to LRP it gets activated and prevents the degradation of the B-catenin.
B-catenin binds to TCF and removes Groucho leading to the activation of Wnt target genes.
