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bio d103
bio d103
70
Bartending
Undergraduate 3
12/08/2009

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Term
Summary of mechanism of action of steroid, thyroid, retinoid hormone
Definition

unbond hydrophobic hormone floats into the membrane then bind to intercelluar receptor, then transcription then translation ...

Also use 2nd messenger

Term

 

žSteroids:

 

Definition

 

¡Cytoplasm
¡NLS: masked by Hsp90
¡Binding of ligand stimulate movement into nucleus to bind DNA

GFP

 

Term

 

žT/R/Vit D:

 

Definition

 

¡Nucleus
¡NLS : unmasked
¡ Acts as a repressor of DNA transcription

 

Term
GTP-binding proteins (aka GTPases or G-proteins)
Definition

bind and hydrolyze GTP. While hydrolyzing GTP, these proteins convey a signal to other components of the intracellular signaling apparatus.

GTPases participate in many cellular activities:
-
Membrane traffic, e.g. Arf, Rab, Sar; monomeric GTPase
-
Nuclear transport, e.g. Ran; monomeric GTPase
-
Regulation of the cytoskeleton, e.g. Rho; monomeric GTPase
-
Protein synthesis, e.g. EF-Tu; monomeric GTPase
-
Protein translocation in ER, e.g. SRP; monomeric GTPase
-
Signal transduction, e.g. Ras, monomeric GTPase
-
Signal transduction, e.g. Galpha+beta+gamma, heterotrimeric GTPase
Term
p53
Definition

Lecture 19 – Cell Signaling I

is a protein that executes all of these functions and is

mutated in more than 50% of human cancers

 

Term
Ras
Definition

Lecture 19 – Cell Signaling I

A point mutation in Ras, a monomeric GTPase, occurs in approximately 1 in 4 human tumors - example of a dominant mutation. A point mutation in the RAS gene (most commonly at G12 or Q61 ) can result in production of Ras protein that has reduced GTPase activity.— This will result in prolonged signaling by the mutated Ras protein.

 

Term
Rb
Definition
Loss of function of Rb, a negative regulator of cell cycle, occurs in non- hereditary retinoblastoma - example of a recessive mutation
Term
GEF
Definition
guanine nucleotide exchange factor (stimulates exchange of GDP for GTP, helps turn GTPase on)
Term
GDI
Definition
guanine nucleotide dissociation inhibitor (prevents loss of GDP from GTPase, helps keep GTPase off)
Term
GPCR-g-protein coupled receptor
Definition
-Signal transduction, interact with heterotrimeric GTPasee.g. GaGby,
-act as GEF
-GEF and stimulate Gα subunit

Gα subunit can either dissociate or stay bound to Gβγ subunits

-Effector protein is usually an enzyme
i.e. Adenylyl cyclase
-1000 possible trimeric G-protien: 20 alpha, 6 beta and 12 gamma
Term
steps of GTPase signal transduction
Definition
1. rate determining-GEF dissociate GDP.
2. fast- binding of GTP, change confirmation of a GTPase for the downstream target..like adenylyl cyclase, or GAP
3. GTP hydrolysis: GAP increase the rate of hydrolysis, during which GTPase generate the signal. irresible and slow---this step is timer
4. dissociation of Pi---fast, inavtigating the GTPase.
5. GDP remain bound
Term
GAP
Definition
GAP increase the rate of hydrolysis, during which GTPase generate the signal. GTPase activating protein
Term
how do GTPase transduct signals?
Definition
monomeric GTPases transduce signals by functioning as timers.
-hetermeric GTPase transduce signals via effect on a downstream target, such as an enzyme, or ion channel
Term
examples of important events regulated by G-Protein coupled receptors ?
Definition
e.g. control of fluid absorption, olfaction, vision, blood pressure etc
Term
effector of GTPase?
Definition
Effector is usually an enzyme (e.g. adenylyl cyclase, phospholipase C, cGMP phosphodiesterase), but sometimes is not - e.g. an ion channel.
Term
How are heterotrimeric GTPases turned on ?
Definition
1. 7 transmembrane receptor are associated but inactive G-protein.
2. signaling molecule binds to receptor then there is a conformational change in G-alpha subunit.
3. receptor act as GEF. a subunit exchange GDP to GTP
4. signal pass on
Term
There are four major targets for activated trimeric G-proteins
Definition

adenylyl cyclase

phospholipase C

cGMP phosphodiesterase

K+ ion channel...
Term
What subunit is activated in hetermoic GCPR?
Definition
usually alpha, but an be beta and gamma in K+ channel, K channel also is the only one that doesn't use 2nd messenger
Term
3 ways of GTPase signaling being terminated.
Definition

by decreasing of ligand: For Gs GPCRs, the affinity of the receptor for ligand decreases when GDP bound to the Gs subunit is replaced by GTP. This is a simple form of negative auto-regulation.

by RGS act as a GAP: GTP bound by a G subunit is rapidly hydrolyzed by the G subunit, which results in downstream signaling being turned off. This process is often accelerated by a regulator of G-protein signaling (RGS) protein.

by downstream product: cAMP phosphodiesterase (PDE) hydrolyzes cAMP, which shuts off downstream signaling.
Term
Giα :Whooping Cough
Definition
:Whooping Cough
Term
3 ways of GTPase signaling get terminated at the receptor level
Definition
-getting tired of being bind(negative regulation)
-arresin: induce sequestration or degradation.
-removal of stimulus
Term
Gsα:
Definition
responsible for cholera toxin. and Pseudohypo- parathyroidism
Term
2nd messenger
Definition
Small; diffuse rapidly
Changes of concentration  signal transmission

Diverse:
inorganic, cyclic NT, lipids and gas
Hydrophilic or hydrophobic
PM or cytosol
Term
kinds of 2nd messenger...
Definition
inorganic ion (Ca2+)
–cyclic nucleotides (cAMP, cGMP)
–lipids (diacylglycerol; DAG)
–gas (nitric oxide)
Term
Adenylyl cyclase - an effector enzyme that produces cAMP
Definition
an effector enzyme that produces cAMP
-Activation of target gene expression via PKA / CREB
-2 inhibitory and regulatory subunits on PKA...
Term
CRE, CREB ,CBP
Definition
CRE - cAMP Response Element
CREB – CRE Binding protein (binds to CRE sequences)
CBP – CREB binding protein
Term
Cyclase –
PDE – phosphordiasterases
Definition
Cyclase – make
PDE – degrade
Term
Place the stages of meiotic prophase into their correct order.
Definition
e. Leptotene, zygotene, pachytene, diplotene, diakinesis
Term
phospholipase C
Definition
cleave PIP2 and produce IP3(hydrophilic) and DAG(hydrophobic)-IP3 binds to IP3 receptor on the surface of ER ----release of CA2+---Ca2+ and DAG bind to PKC(protein kinase C)
Term
way to turn off phospholipase b activity
Definition
IP3 is rapidly dephosphorylated by lipid phosphatases to form IP2 .

IP3 can also be phosphorylated by lipid kinases to form IP4 . (IP4 can also function as a signaling molecule, but it's targets are currently poorly understood).

Ca2+ that has entered the cytosol is rapidly pumped out of the cell.

Special (TRP) channels at plasma membrane dock with ER to replenish Ca2+ in ER in a rapid manner.
Term
Rate of diffusion of second messenger
Definition
varies; e.g. Ca2+-low; cGMP/cAMP, IP3 - high.Turn off by lipid phosphatases or kinases
Term
except GCPRs, comparisons of others
Definition

TGFβ-family receptors Smads

Cytokine receptors JAK's / STAT's

Receptor tyrosine kinases Ras / MAP kinase
Term
GCPRs participants.
Definition
CREB, PKA
Term
Receptor tyrosine kinasese participants
Definition
Ras/MAPs, phosphorylation by cytosolic kinase in nucleus or cytosol
Term
TGFb participants
Definition
Smads, phosphorylation in cytosol by activated receptor
-The major function of TGF- proteins is to inhibit cell proliferation.
Receptors:
Type I, Type II & Type III
Signals are conveyed by Smads
R-Smad, co-Smad and I-Smad
Associate with TFs

Inactivation: I-Smad or inhibitors of TF
Interaction with Ski and Sno
Signaling reduce steady states
Term
enzyme-linked cell surface receptor properties
Definition
-ligand-binding domain outside..like GPCR
-single-pass
-enzyme-linked
-enzyme is either kinase or phasphatase(kinase more likely), specificity for a tyrosine, serine or threonine.
Term
cytokine receptor participants:
Definition
JAK/STATs
Term
tgfb receptor
Definition

Receptors are hetero-tetramers of two each of type I and type II subunits; each subunit has intrinsic serine/threonine kinase activity.

Type III receptor binds TGF- and can either present it to type II receptor or can sequester ligand.•
Receptors are hetero-tetramers of two each of type I and type II subunits; each subunit has intrinsic serine/threonine kinase activity.

Type III receptor binds TGF- and can either present it to type II receptor or can sequester ligand.
Term
type of smad
Definition
Three functional classes of Smad proteins - Receptor regulated (R-) Smad, co-Smad, Inhibitory (I-) Smad.

Smad proteins heterotrimerize and bind to DNA, thereby recruiting additional factors requried for regulation of target gene expression.

TGF- signaling negatively regulated by Inhibitor (I-) Smads, or by recruitment of inhibitors of transcription e.g. histone deacetylases.
Term
how are smads phosphorylated?
Definition
Ligand either binds directly to type-II receptor (RII), or may be presented to RII by RIII.
Ligand binding to RII stimulates ligand+RII to bind to RI. RII phosphorylates RI. Phosphorylated RI in turn phosphorylates R-Smad.
Phosphorylation of the R-Smad at three serines at the C- terminus changes its conformation (sound familiar ?), which exposes a NLS signal.
Phosphorylated Smad3s can associate via interaction of their MH2 domains and the phosphorylated serines.
-•
Importin-β forms a complex (step 4) with two molecules of phosphorylated Smads (Smad3 here), plus one molecule of non-phosphorylated Smad (Smad 4, a co-Smad).

Following nuclear import (step 5), Importin β undocks (step 6), and the Smad trimer associates with TFE3 (step 7; a co-transcription factor) to form a transcriptional activation complex at specific target sites in the genome.

Nuclear R-Smads are continuously dephosphorylated and exported from nucleus Thus the concentration of Smads in nucleus is directly proportional to the amount of TGF-  receptor signaling occurring at cell surface at that time.
Term
p27
Definition
:act as inhibitors of Cdc25
Term
wee1 & cdk?
Definition
A = Cyclin B, B= Cdk activating kinase (CAK), C = wee1 (inhibitory kinase), E= Cdc25
(activating phosphatase). Complex D is phosphorylated by CAK (+) and wee-1 (-).
a. M-Cdk complex is formed through expression and build up of cyclin B. The complex
has minimal activity until phosphorylated by CAK on the T-loop. However, wee-1 keeps
the complex inactive by phosphorylating on two additional sites of the T loop.
b. As the complex concentration builds, a threshold is reached where the small amount of
kinase activity will phosphorylate and activate Cdc25 (phosphatase) by positive
feedback. Cdc25 removes the inhibitory phosphates  further activation. M-Cdk
activity also inhibits wee-1 (+ve feedback)  promoting further activity.
c. Downstream targets of M-Cdk include lamins, nuclear pore complex etc.
d. DNA damage induces p53  increased p21 expression which acts as a CKI by binding
to M-Cdk (or p27 which act as inhibitors of Cdc25 keeping these components inactive
Term
p15
Definition
proteins that inhibit entry into the cell cycle (e.g. p15).
Term
tgfb
Definition
Ligand can bind to RII or delivered by RIII to RII  binding of RI
RII phos RI phos R-Smad (3 serines @ C-terminus)  expose NLS
2 R-Smad-Pi interact via MH2 domains and phos.serines the recruit co-Smads
Importin β bind onto R-smads  nuclear import  associate with TFE3 (co-TF)
Term
Which has no direct effect on regulation of PKA activity
Definition
concentration of adp
Term
Cytokines receptor
Definition
Binding of ligand dimerizes receptors,
-JAK can phosphorylate a tyrosine
-this causes an additional conformational change in the lip domain which allows each JAK to become fully active.

Activation of a lip domain by relatively weak kinase activity is a common mechanism whereby kinases can be activated.
Term
how to stop JAK/s activity?
Definition
SH2 domain
SHP1  binds to phosphotyrosine site of receptor.. And binds to JAK to inhibit it
Suppressor of Cytokine signaling (SOCS): binds to JAK and phosphotyrosine… recruit E3 ubiquitin ligase
Term
phosphatidylinositol PI
Definition
PI is an example of phosphoinositide (which is from phosphatidylinositol)
 Sugar (inositol) that is phosphorylated and attached to glycerol (2FA tails)

It’s a phospholipid!
Term
scaffolding proteins
Definition
Scaffolding proteins provide specificity of signaling, and facilitate negative feedback control of local concentration of cAMP

-
Term
terminal differentiation
Definition
a. To prevent there being too many cells of a
given type
b. Makes cancerous progression difficult
c. Useful for cell specialization
d. Allows control of spatial organization of
cells
Term
The unidirectional and irreversible passage through the cell cycle i
Definition
first Cdk Kinase Inhibitor (CKI)---sci1 is symthesized at G1 phase, to be a checkpoint, in which p53 transcripe p21, which transcripe the cdk inhibitor, inactivating g1-s-cdk.

brought about by the degradation of critical protein molecules at specific points in the cycle. Examples are the proteolysis of cyclin B in late anaphase, and proteolysis of the S-phase CDK inhibitor(sic1) at the start of S-phase. Cyclin B is polyubiquitinated by APC, whereas the S-phase CDK inhibitor is polyubiquitinated by SCF. The polyubiquitinated substrates are subsequently degraded by proteasome.Cdc20 binds to APC – initiate anaphase. Activation of M-Cdk/Cyclin:
Wee1: inactivating kinase
Cdc25: activating phosphatase
Positive feedback loop
Cdc14 dephosphorylate Cdh1 binds to APC  exit mitosis
Deactivate M-cyclin/Cdk complex by ubiquitination on ‘destruction box’
Term
p21
Definition
is a CKI that binds and inhibits the activity of the cyclin-CDKs, usually in response to damaged DNA.
Term
PAI-1
Definition
an inhibitor protein which prevents other proteases from degrading the extracellular matrix.
Term
cyclin and CDks
Definition
Cyclin - a protein whose steady-state level of expression varies during the cell cycle. Cyclin has no
intrinsic kinase activity.
Cyclin-dependent kinase (CDK) - this protein has kinase activity, but kinase activity requires the cdk to
being bound by cyclin.
Term
how growth factor take part?
Definition
Growth factors bind to extracellular
receptors.
• Activate phosphoinositol-3-kinase
(plus other pathways).
• Activates downstream kinases - e.g.
TOR.
• eIF4E is rate limiting in translation
of mRNA.
• Increase in steady-state level of
eIF4E and RS6K leads to rapid
increase in synthesis of proteins
and molecules required for cell
metabolism and cell growth.
Term
how mitogen works
Definition
bind to extracellular receptor--> MAP kinase ---> transcription of myc, which encode a transcription factor.--> increase g1-cyclin, and activates G1-cdk. -->Rb binds and sequester transcription factor E2F-->blocking growth. g1-cyclin/cdk complex phosphorylate Rb and inactivates it.--> E2F now expresses.
Term
sci1
Definition
S-cyclins are in active because it is bind to .sci1, the inhibitor
Term
S-cyclins how regulated?
Definition
S-cyclins are in active because it is bind to Sic1., the inhibitor
To Activate S-phase cyclins:
1. When concentration of G1 cyclins is relatively high, they result in
removal of Sic1 from S-CDK by phosphorylating Sic1
2. Destruction of Sic1 by SCF-mediated ubiquitination and degradation
Term
cdc6 in S phase
Definition
In S-phase, S-Cdk phosphorylates Cdc6 displaces Cdc6
from the origin of replication, allowing DNA replication to
initiate. Phosphorylated Cdc6 cannot bind to origins of
replication, and mediates its own degradation. These events
prevent regions of the chromosomes from being replicated
more than once per cell cycle
Term
G2 Checkpoint
Definition
G2 DNA damage checkpoint is activated.
• This cascade temporary inactivates M-phase cyclin-dependent kinases via synthesis of
cyclin protein kinase inhibitors (CKI's).
Term
going to anaphase...
Definition
securin: bind to seperates, keeps it inactive so it can’t degrade cohesin. MCDK phosphorylate the ubiquitinates ligase APC-Cdc20, which is activated by Mad2 . M-Cdk level is high enough, phosphorylate ACP, APC ubiqulates securin, enables it to release seperates, release of seperates then cuts all the ring.
Term
summary of cell cycle degradation and stuff
Definition
• G1-CDK and G1/S-CDK:
a. phosphorylate Rb release transcription factor E2F transcription of S-phase
genesmake S-cyclin protein and others for (e.g. ) DNA synthesis
b. phosphorylate Sic1 (a CKI that blocks S-Cdk activity)Sic1 recognized and targeted
for destruction by SCFS-CdK activated
• S-CDK
a. Initiate DNA replication by phosphorylating Cdc6, releasing it from DNA OR and
allowing replication to start. This phosphorylation also targets Cdc6 for destruction.
• M-CDK
a. phosphorylates the ubiquitin ligase called Anapahse promoting complex (APC)-cdc20,activated by mad2,
activating it. APC then targets both Securin (which protects linkages that hold chromosomes
together), and also S- and M-cyclins (this allows completion of M-phase).
Term
Adenylyl cyclase
Definition
an effector enzyme that produces cAMP. High turnover rate
Cyclase – make
PDE – degrade
Term
Phospholipase C
Definition
2nd messenger that cleave PIP2 and produce IP3(hydrophilic) and DAG(hydrophobic)-IP3 binds to IP3 receptor on the surface of ER -release of CA2+Ca2+ and DAG bind to PKC(protein kinase C)
Term
Giα
Definition
Whooping Cough
Term
Gsα:
Definition
cholera toxin. and Pseudohypo- parathyroidism
Term
arresin
Definition
adaptor protein that prevents ligand from binding.
Term
GM130
Definition
during prophase, work with P115 during golgi transportation of vesicles. But when phosphorylated by M-CDK and P9 during prophase, it doesn’t interact with p115 anymore to arrest golgi fusion.
Term
gm130
Definition
GM130: during prophase, work with P115 during golgi transportation of vesicles. But when phosphorylated by M-CDK and P9 during prophase, it doesn’t interact with p115 anymore to arrest golgi fusion.
Term
COP-1
Definition
: mediate budding of vesicles by golgi, and is not affected by the phosphorylation of GM130.
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