• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

Card Range To Study

through

image

Play button

image

Play button

image

Progress

1/44

Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

44 Cards in this Set

  • Front
  • Back
Receptor Tyrosine Kinases (RTKs)
- cell surface receptors with tyrosine-specific kinase activity
growth factors/hormones and RTKs
growth factors/hormones (PDGF, NGF, EGF, GFG, Insulin) bind to RTKs, stimulating the tyrosine kinase activity of the receptor -> cascade of signals which regulate cell growth, proliferation, differentiation, cell survival, and cell metabolism.
Structure of RTK:
- ligand-binding extracellular domain
- single hydrophobic transmembrane alpha helix
- cytosolic domain that contains the region with tyrosine kinase activity
ligand binding to RTK:
- causes receptor dimerization
- autophosphorylation and activation of the receptor
Cancer cells:
contain defective growth factor receptors which in most cases are constitutively-activated in the absence of a ligand.
Ras:
- monomeric GTP-binding protein with GTPase activity.
Active and inactive Ras
active: present in the GTP-bound form (Ras.GTP)

inactive: GDP bound (Ras.GDP)
Difference between Ras and G proteins
- Ras does not directly interact with the RTK, as oppose to G-proteins that are directly coupled to their receptors
- Ras requires a couple of helper proteins to interact with GTP and GDP
inactivate Ras
- hydrolysis of bound GTP
- requires the binding of a GTPase activating protein (GAP) that enhaces its GTPase ability.
Ras disassociate from GDP
needs guanine exchange factor (GEF)
GTPase super family of proteins:
- proteins that switch between GTP and GDP bound forms
- G proteins, Gsalpha, Gialpha, Ras, Rab proteins (regulate fusion of intracellular vesicles, Rho proteins (regulate the actin cytoskeleton).
Oncegenic forms of the Ras protein
- cancers of lung, colon and pancreas
- - oncogenic Ras protein binds to GTP but no longer has the GTPase activity -> constitutively activateld in the absence of a growth factor.
cytosolic proteins that link TRK with Ras:
- GRB2

- SOS
GRB2
contains Src-homolgy domains (SH2 and SH3)
- functions as an adaptor protein
- following RTK activation, GRB2 relocalizes near the membrane and binds to a specific phosphotyrosine residue in the activated RTK via a SH2 domain, and to SOS via its two SH3 domains which contain proline-rich sequences
SOS
- functions as a GEF and facilitates the conversion of membrane-bound RAS.GDP to Ras.GTP.
other than SOS and GRB2, RTK activation also leads to:
binding of GAP to specific phosphotyrosines in the RTK, and GAP, in turn, facilitates conversion of Ras.GTP -> Ras.GDP form.
Ras is bound to the cytosolic face of the membrane:
through a farnesyl group
- farnesylation of Ras is importaant step in Ras activation
kinase cascade following binding of a growth factor to a specific RTK
activated RTK leads to formation of Ras.GTP -> binds to amino-termnus of Raf
- activated Raf binds to and phosphorylates MEK, which is a dual kinase for MAPK, causing phosphorylation of MAPK at tyrosine and serine/threonine residues
activated MAPk:
translocated to nucleus -> phosphorylates and activates a variety of transcription factors regulating gene expression associated with cell growth, proliferation and cell survival
MAPK phosphorylates transcription factor:
TCF (ternary complex factor) and a serum response factor (SRF)
- these factors bind to a specific DNA element, Serum Reponse Element (SRE) in the promoter regions of a variety of genes, enhancing transcription.
After activation (phosphorylation by MEK), MAPK:
enters the nucleus where it sphosphorylates ternary complex factor (TCF) and serum response factor (SRF) which are transcription factors
transcription factors:
bind to the DNA at serum response elements (SRE) to promote transcription
Pathway involving MEK and MAP
Raf-1->MEK->MAPK-.TCF->SRE
RTH-activated PI3-K pathway important in:
cell growth, proliferation and cytoskeletal rearraangements.
Phosphatidylinositol-3-kinase (PI3-K)

structure:
heterdimeric molecules composed of a regulatory subunit (p85) and a catalytic subunit (p110), encoded by different genes.
PI3-K catalyzes:
the phosphorylation of inositol containing lipids (phosphatidylinositols) at their 3-positions.
PI3-K regulate:
levels of membrane-bound phosphoinositides (PIP and PIP2),
PI3-K generate:
generates a new second messenger PIP3.
AKT
downstream effector of PI3-K
- recruited to the membrane by a direct contact of its pleckstrin homology (PH) domain (a lipid-protein interaction domain) with PIP3.
AKT at the membrane:
is phosphorylated by 3-phosphoinositide-dependent protein kinases (PDK1 and PDK2).
PTEN
- tumor suppressor-3-phosphatase
- dephosphorylate PIP3 at D3 position -> shuts off the binding and activation of AKT
IRS
insulin receptor substrate
- the activated RTK binds an IRS bringing about its phosphorylation
- the IRS binds to PI3-K
TRK-PI3-Kinase-AKT pathway
activated RTK -> phosphorylation of IRS -> binds to PI3-K -> regulates levels of PIP and PIP2 and generate PIP3 -> PIP3 recruits AKT (Protein kinase B) -> AKT phosphorylated and propagates signal -> PIP3 turned off by dephosphorylation by PTEN, which also causes AKT to dissociate
RET receptor tyrosine kinase

structure:
- transmembrane region, - intracellular kinase domain, and a cysteine-rich extraceulluar region.
difference between RTKs and RET and how it works:
RET requires a ligant and a coreceptor (adaptor) for activation.
- one of the four coreceptors (GFRalpha-1 - GFRalpha-4) binds to one of the four ligands (glial cell line-derived neurotrophic factor GDNF, neurturin NTN, artemin ART, persphin PSP), and the complex binds to RET, initiating receptor dimerization, autophosphorylation and phosphorylation of other substrates.
activated RET interacts with:
adaptor molecules containing SH2 domains (GRB2, GRB7, Shc).

RET signals lead to activation of Ras-MAPK for growth and differentiation, PLC gamma for calcium release, and PI3-K for motility and survival. athways.
mutations in RET proto-oncogenes has been demonstrated in:
multiple endocrine neoplasia type 2 (MEN 2A/B) and familial medullary thyroid carcinoma (FMTC)
MEN 2
autosomal dominant inheirted cancer syndrome characterized by medullary thyroid carcinoma (MTC), phenchromocytoma (PC) and hyperparathyroidism (HPT).
activation of insulin receptor tyrosine kinase follow:
the Ras-Raf-MAPK pathway to modulate gene expression.
pathway for insulin stimulating the uptake of glucose and glycogen synthesis:
1. IRS-1, Ped by the insulin receptor, activates PI-3K by binding to its SH2 domain. PI-3K converts PIP2 to PIP3.
2. PKB bound to PIP3 is Ped by PDK1. Thus activated, PKB P GSK3 on a Ser residue, inactivating it.
3. GSK3, inact by P, acnnot convert GS to its inactive form
4. synthesis of glycogen increase
5. PKB stimulates movement of GLUT4, increasing uptake of glucose
Mechanism for insulin-responsive Ras-Raf-MARPK pathway and modulation of gene expression:
1: insultin receptor binds insultin -> autophosphorylation on its carboxyl-terminal Tyr residues
2. insulin receptor phosphorylates IRS-1 on its Tyr residues
3. SH2 domain of Grb2 binds to P-Tyr of IRS-1. SOS binds to Grb-2, then to Ras, casuing GDP release and GTP binding to Ras
4. activated Ras bindis and activates Raf-1
5. Raf-1 phosphorylates MEK on two Ser residues, activating it. MEK phosphorylates MAPK on a Thr and a Tyr residue, activating it.
following fasting:
- blood glucose level falls below the normal level
- pancreatic alpha cells secret glucagon
- glucagon binds to its receptor on liver cells -> increase cAMP -> degradation of glycogen
glucose is taken from the blood via:
RTK pathway
glucose is put back into the blood:
as a result of a G-protein pathway.