5 - Cell Signaling (Part 2) Flashcards
transmembrane proteins with their ligand-binding domain on the outer surface of the plasma membrane
enzyme-coupled receptors
has intrinsic enzyme activity or associates directly with enzyme
cytosolic domain
each subunit of an enzyme-coupled receptor has typically how many transmembrane segments
one transmembrane segments
- most common class of signaling by enzyme-coupled receptors
- where many extracellular signal proteins act through
receptor tyrosine kinase (RTKs)
How many human RTKs are classified into 20
structural subfamilies
60 human RTKs
each 20 structural subfamilies are dedicated to its complementary family of ____ ____
protein ligands
the binding of the signal protein to
the ligand-binding domain on the
extracellular side of the receptor
activates the _____ _____ ____ on the cytosolic side?
tyrosine kinase domain
the binding of the ___ protein to
the ___-binding domain on the
extracellular side of the receptor
activates the tyrosine kinase
domain on the cytosolic side
signal
ligand
activation of the tyrosine kinase
domain on the cytosolic side leads to?
phosphorylation of tyrosine side chains on the cytosolic part of the receptor
phosphorylation of tyrosine side chains creates what
phosphotyrosine docking sites
phosphorylation → ___________
docking sites
phosphotyrosine
ligand binding causes the receptors to ?
dimerize
causes the receptors to dimerize
ligand binding
ligand binding causes the receptors to
dimerize, bringing the two cytoplasmic
_____ _____together and thereby
promoting their activation →
_________
kinase domains
phosphorylation
dimerization brings the kinase domains close to each other in an orientation that allows them to phosphorylate each other on specific tyrosines
insulin receptor
phosphorylation of the kinase domains promote?
conformational changes that fully activate both kinase domains
the kinase is not activated by phosphorylation but by conformational changes brought about by interactions between the two kinase domains outside their active sites
epidermal growth factor (EGF),
Once the kinase domains of an RTK dimer are activated, they phosphorylate?
multiple additional sites in the cytosolic parts of the receptor
phosphorylation of multiple additional sites in the cytosolic parts of the receptor creates high-affinity ____ ___ for intracellular signaling proteins
docking sites
signaling proteins binds to a particular __________ site on the activated receptors
phosphorylated
why signaling proteins binds to a particular phosphorylated site on the activated receptors
it contains a specific phosphotyrosine-binding domain that recognizes surrounding features of the polypeptide chain in addition to the phosphotyrosine.
Once bound to the activated RTK, a signaling protein may become what?
phosphorylated on
tyrosines and become activated
serves as a switch to trigger the assembly of an intracellular signaling complex
receptor phosphorylation
families of monomeric GTPases
Ras superfamily
relay signals from cell-surface receptors
Ras families
can coordinately spread the signal along several distinct downstream
signaling pathways, thereby acting as a signaling hub.
Ras or Rho family member
can coordinately spread the
signal along several distinct
downstream signaling
pathways
signaling hub
three major, closely related Ras proteins in humans
H-
K-
N-Ras
contains one or more covalently attached lipid
groups
Ras proteins
required when RTKs signal to the nucleus to stimulate cell proliferation or
differentiation
Ras protein
Ras protein is required when RTKs signal to the nucleus to stimulate?
cell proliferation or
differentiation
cell proliferation or differentiation require changes in?
gene expression
express hyperactive mutant forms of Ras
30% of human tumors
Ras functions as a _______ ____ , cycling
between two distinct conformational states
molecular switch
regulate Ras activity by influencing its
transition between active and inactive
states
two classes of signaling proteins
two classes of signaling proteins regulate Ras activity by influencing its
transition between?
active and inactive
states
stimulate the dissociation of GDP and the subsequent uptake of GTP from the cytosol, thereby activating Ras
Ras guanine nucleotide exchange
factors (Ras-GEFs)
Ras guanine nucleotide exchange
factors (Ras-GEFs) stimulate the dissociation of ___ and the subsequent uptake of ___ from the cytosol, thereby activating ___
GDP
GTP
Ras
increase the rate of hydrolysis of
bound GTP by Ras, thereby inactivating Ras
Ras GTPase-activating proteins (Ras-GAPs)
Ras GTPase-activating proteins (Ras-GAPs) inactivate ___
Ras
resistant to GAP-mediated GTPase stimulation
Hyperactive mutant forms of Ras
Hyperactive mutant forms of Ras are
resistant to ___-______ ______
GAP-mediated GTPase
how do RTKs normally activate Ras?
either activate a Ras-GEF or inhibit a
Ras-GAP
has a similar effect to the loss of function of Ras itself
loss of function of a Ras-GEF
GEF that mediates Ras activation by RTKs was discovered by genetic studies of eye development in Drosophila, where an RTK called _______ is required for the formation of a photoreceptor cell called R7
Sevenless (Sev)
Sevenless (Sev) is required for the formation of a photoreceptor cell called?
R7
Genetic screens for components of this signaling pathway led to the discovery of a Ras-GEF called
Son-of-sevenless (Sos)
an adaptor protein that links the Sev receptor to the Sos protein
Grb2
Grb2 links the ___
receptor to the ___ protein
Sev to Sos
promotes Ras activation
Sos
Once activated, it activates various other signaling proteins to relay the signal downstream
Ras
usually short-lived
tyrosine phosphorylations and the activation of Ras
quickly reverse the phosphorylations
tyrosine-specific protein phosphatases
induce activated Ras to inactivate itself by hydrolyzing its bound GTP to GDP
Ras-GAPS
To stimulate cells to
proliferate or differentiate, these short-lived signaling events must be converted
into longer-lasting ones
tyrosine-specific protein phosphatases
and Ras-GAPS
three components of this system form a functional signaling module that has been remarkably well conserved
during evolution and is used, with variations, in many different signaling contexts
mitogen-activated protein kinase
module (MAP kinase module)
MAP kinase module three components
MAPK (Erk)
MAPKK (Mek)
MAPKKK (Raf)
relays the signal
downstream by phosphorylation
MAP kinase
enters the nucleus and phosphorylates one or more components of a transcription regulatory complex
Erk
Erk enters the _____
nucleus
phosphorylation of one or more components of a transcription regulatory complex by Erk activates the what?
immediate early genes
(transcription regulators)
conveys signals from the cell surface to the nucleus and alters
the pattern of gene expression
Ras-MAP-kinase signaling pathways
Ras-MAP-kinase signaling pathways convey signals from the cell ____ to _____ ?
cell surface to
the nucleus
Ras-MAP-kinase signaling pathways alters the pattern of
gene expression
mediates
different responses in the same cell
MAP kinase modules
help prevent crosstalk between parallel MAP kinase modules
scaffold proteins
How many MAP kinase modules can
operate in a mammalian cell
five parallel MAP kinase modules
five parallel MAP kinase module make use of at least how many MAP kinases, MAPKKs, and
MAPKKK
12 MAP kinases
7 MAPKKs
7 MAPKKK
activated by different kinds of cell stresses, such as ultraviolet (UV), heat shock, and osmotic stress
JNK and p38
reduces the opportunities for amplification and spreading of the signal to different
parts of the cell
scaffold strategy
regulate both the actin and microtubule cytoskeletons, controlling cell shape, polarity, motility, and adhesion
Rho family monomeric GTPases
What do Rho family monomeric GTPases regulate?
both the actin and microtubules cytoskeleton
regulation of both the actin and
microtubules cytoskeleton controll what?
cell shape, polarity, motility, and
adhesion
Rho family monomeric GTPases also regulate?
cell-cycle progression
gene transcription
membrane transport
Rho family monomeric GTPases play a key part in the guidance of cell ______ and ____ ___ _______?
cell migration and nerve axon outgrowth
three best-characterized Rho family members
Rho
Rac
Cdc42
activates Rho family
GEFS
inactivates Rho family
GAPs
often bound to guanine nucleotide dissociation inhibitors (GDIs) in the cytosol
inactive Rho family GTPases
inactive Rho family GTPases often bound to?
guanine nucleotide dissociation inhibitors (GDIs)
provides an example of how RTKs can activate a Rho GTPase.
ephrin family
Ephrins bind and thereby activate members of the?
Eph family of RTKs
found on the surface of motor neurons and helps guide the migrating tip of the axon (called a growth cone) to its muscle target
Eph family
One member of the Eph family is found where
surface of motor neurons
migrating tip of the axon is also known as
growth cone
activates the Eph receptor
binding of a cell-surface ephrin
protein
What does binding of a cell-surface ephrin
protein activates
Eph receptor
activation of the Eph receptor cause growth cones to ____
collapse
growth cone collapse; ____ them
from inappropriate regions and
keeping them on track
repelling
activate RhoA (Rhoa-GTP)
Rho-GEF ephexin
It is where major changes in the behavior of a cell tend to depend
change in gene expression
carry out their effects by initiating signaling pathways that change the activities of transcription regulators
extracellular signaling molecules
extracellular signaling moleculescarry out their effects by initiating signaling pathways that change the activities of ?
transcription regulators
controlled in gene expression
less common signaling mechanisms
pathways that depend on regulated ________
proteolysis
do not employ cell-surface receptors but enter the cell and interact directly with transcription regulators to perform their functions
class of extracellular signal molecules
-the daily cycle of light and dark
circadian rhythm
gene expression controlled by _____ rhythm
circadian
- used wildly in animal development
- has a general role in controlling cell fate
choices and regulating pattern formation and continual renewal of tissues
Notch receptor protein
General roles of Notch receptor protein
- controlling cell face choices
- regulating pattern formation
- continual renewal of tissues
Notch receptor protein is best known for production of?
Drosophila neural cells
when a precursor cell commits to becoming a ____ cell → signal to its _______ ______ not to do the same
neural
immediate neighbors
commits to becoming a neural cell
precursor cell
contact-dependent signaling mechanism that is activated by a single-pass transmembrane signal protein called Delta
lateral inhibition
lateral inhibition is activated by signal protein called?
Delta
Delta binds to?
Notch receptor protein
- a single-pass transmembrane protein that requires proteolytic processing to function.
- It acts as a latent transcription regulator
Notch proteins
Notch proteins require ______ ________ to function
proteolytic processing
Notch proteins act as?
latent transcription regulator
binding of ____ → plasma-membrane-bound ______ cleaves off the cytoplasmic tail of Notch → tail translocates into the nucleus to
activated the transcription of ___
response genes
Delta
protease
Notch
cleaves off the cytoplasmic tail of Notch
a plasma-membrane-bound protease
translocates into the nucleus to activate the transcription of a set of Notch response genes
released tail
acts by binding to a DNA-binding protein, converting it from a transcriptional repressor into a transcriptional activator
Notch tail fragment
Notch tail fragment convert DNA-binding protein from transcriptional ____ into a transcriptional ______
transcriptional repressor into a transcriptional activator
undergoes three successive proteolytic cleavage steps
Notch receptor
Notch receptor undergoes three
successive _______ _____ steps
proteolytic cleavage steps
how many successive proteolytic cleavage steps does the notch receptor undergo?
3
In three successive proteolytic cleavage steps of notch receptors, only ___ depend on Delta binding
2
