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Cell Signaling Flashcards

1
Q

Receptor Tyrosine Kinase (RKT)

A

Single pass transmembrane proteins with ligand binding domains outside the cell and protein kinase domain inside the cell

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2
Q

What can RKT control?

A

rate of cell proliferation and growth with the exception of insulin
*insulin does not control cell growth but has the same receptors as cell growth ligands

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3
Q

Cell growth receptor ligands for RKTs

A 
EGF (epidermal)
PDGF (platelet)
FGF (fibroblast) 
VEGF (vascular endothelial) 
CSF (colony stimulating factor)
IGF1 (insulin like growth factor)
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4
Q

1st step of RKT signaling

A

Receptor dimerization due to ligand binding

*ligands can either be dimers or monomers that cause conformational changes in the receptor and its dimerization

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5
Q

What happens after dimerization of the receptor?

A

Leads to self-phosphorylation of the receptor on multiple tyrosine residues

The kinase domain of one receptor subunit phosphorylates the tyrosine’s on the other subunit

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6
Q

How does binding lead to dimerization?

A

Binding causes conformational changes which propagates thru the membrane and forces tyrosine kinases closer to each other

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7
Q

SH2 Domains

A

Large protein domains that recognize phosphotyrosine and bind to the phosphorylated receptors at these sites

(can also recognize several amino acids C terminal side of the tyrosine)

-Y-X-X-hy-

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8
Q

PTB Domains

A

recognize phosphorylated tyrosines and several AA at the N terminal side of the tyrosine

-N-P-X-Y-

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9
Q

SH3 Domains

A

recognize proline rich sequences

-P-X-X-P-X

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10
Q

PH Domains

A

recognize phosphorylated lipids

-PI3,4P2, PI3,4,5P3

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11
Q

RKT and SH2 Domains

A

Binding of SH2 Domain proteins to the activated RKT leads to activation of different downstream pathways

Each RKT contains several P-Tyr and so it can interact with several different SH2 proteins at the same time

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12
Q

what does the MAP Kinase pathway do?

A

An example of an RKT pathway

Mediates cell proliferation (increase in cell number) and cell growth (increase in cell size)

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13
Q

Ras- basic pathway

A

GTPase protein
Mutated Ras found in 30% of mammalian tumors

RasGTP RasGDP

Gap activates forward reaction and GEF activates reverse
Once RasGDP, need GEF to bring back the GTP b/c thru GEF Ras binds to GTP since [GTP] 100x more than [GDP] in the cell

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14
Q

Plasma membrane Ras

A

Involved in signaling
Farnesyl is attachd to C terminal of Ras so that Ras is attached to plasma membrane thru this hydrophoic anchor

can also be attached via fatty acid residue

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15
Q

G2B2

A

Adaptor protein

SH3-SH2-SH3 domains

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16
Q

MAP kinase pathway

A

Binding of the SH2 domain of G2B2 to the active RKT leads to plasma membrane recruitment of protein SOS (via its SH3 domain)

SOS facilitates the binding of GTP to Ras which activates Ras (RasGTP) making it tethered to the cell membrane

Activation of MAP kinase pathway

Activate Raf recruits Mek thru phosphorylation

Mek phosphorylates ERK

ERK dimerizes and is translocated to the nucleus where it phosphorylates transcription factors and activates transcription of early response genes

Products of these activated genes stimulate expression of other genes required to progress through the cell cycle

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17
Q

SOS

A

GTP/GDP exchange factor for Ras

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18
Q

Raf

A

Serine threonine kinase which is activated at the PM when

1) Ras binds to the PM
2) dimerization and phosphorylation occurs

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19
Q

PI3K

A

Phosphatidyl Inositol 3-Kinases are lipid kinases that phosphorylate PI

PI is the ubiquitous component of the membrane

Involves downstream protein synthesis and cell growth

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20
Q

PI3K 1A

A

Has 2 SH2 domains
Binds P-Tyr domains

1) regulatory subunit: p85
2) catalytic subunit: p110

p85 inhibits the activity of p110
under basal conditions, this enzyme is not active

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21
Q

PI3K pathway

A

PI3K binds to two P-Tyr domains in the active RTK –> changes conformation of the enzyme –> activates and produces PIP3 in the plasma membrane

PIP3 activation –> PDK1 and Akt (serine threonine kinases) recruited to the membrane via their PH domains causing a conformational change in Akt

Conformational change causes p85 subunit to no longer inhibit p110 on Akt

PDK1 phosphorylates Akt and activates it

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22
Q

PI3K pathway 2

A

p85 subunit on PI3K has 2 SH2 domains which bind to two neighboring phosphorylated tyrosines –> changes conformation of enzyme –> no longer inhibits p110 –> PI3K phosphorylates at position 3 of PI on the membrane

[PI3,4,5,P3] goes up and this binds to proteins with specific PH domains aka Akt

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23
Q

Activation of Akt

A

Akt=PKB

PH domain is structured so that it masks the kinase activity on Akt

Once Akt binds to [PI3,4,5,P3] on the membrane, it unfolds and the kinase portion of the enzyme is free

Binding of Akt to PM and phosphorylation of the kinase and hydrophobic tail leads to Akt activation

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24
Q

Function of Akt

A

Phosphorylates and inhibits multiple substrates like BAD (apoptotic)

Phosphorylates multiple targets related to glucose metabolism and energy homeostasis

25
Akt in parallel with ERK pathway
Akt phosphorylates and inhibits TSC2 together with TSC1 which is a GAP for Rheb --> amount of GTPRheb increases since no longer being exchanged out GTP/Rheb activates serine threonine protein kinase mTORC1 --> increase in protein biosynthesis and cell growth
26
mTORC1
Upregulates protein translation
27
TSC
Tubular Sclerosis Complex - disease from somatic mutations in TSC1 or TSC2 - formation of benign tumor (size of the cells in the tumor are super large b/c
28
How does the PI3K pathway affect MAP kinase pathway?
MAP pathway stays the same...unaffected
29
PLCγ
2 SH2 domains and a PH domain that helps to recruit it to the plasma membrane
30
PLCγ Pathway
Once at PM + phosphorylation at its receptor, hydrolyzes PIP2 (cleaves it) and produces IP3 and DAG
31
IP3
Inositol triphosphate Very soluble Binds to specific receptors in ER and releases Ca2+ in the cytosol
32
DAG
Diacyl Glycerol | Stays at PM and activates PKC's
33
Erb B fam
Erb B receptor family These receptors can either homo or heterodimerize after binding to multiple ligands Erb B expressed in breast, colorectal, and gastric cancers *dimerization can lead to constant activation of the mutant receptor in absence of the ligand
34
Monoclonal antibodies
THERAPY mABs at an extracellular portion of a mutant receptor can compete with ligands from binding to receptor and deactivate it
35
Cancer therapy
specific inhibitors of the kinase domain
36
GPCR
G protein coupled receptors are largest family of receptors with enormous diversity of ligands Can bind to neurotransmitters, odorants, taste ligands, even light All have 7 transmembrane (7TM) proteins with N-terminus located outside the cell and the C-terminus inside the cell
37
Ligand binding for GPCR
Hydrophilic ligands bind to the N terminus or extra cellular loops Hydrophobic ligands diffuse into the transmembrane and bind to the core of the receptor
38
Trimeric G proteins
Therese proteins are anchored to the PM by hydrophobic links alpha- has a Ras like domain and is a GTPase beta/gamma
39
GTPase activity of alpha G protein
can dissociate from beta/gamma GDP form: bound to beta/gamma GTP form: dissociates from beta/gamma *even when dissociated, both units stay on the PM thru hydrophobic links (fatty acid?)*
40
Interaction between GPCR and G protein
Ligand binding changes conformation of 7-membrane GPCR....works as GEF and facilitates the exchange of GDP for GTP at the alpha subunit --> activation of alpha Dissociation of alpha from beta/gamma Both complexes go their downstream targets and activate different pathways Eventually, alpha subunit hydrolyzes GTP molecule with the help of a RGS protein alpha/beta/gamma
41
Downstream targets for beta/gamma
-activates PI3K 1B (same pathway as PI3K 1A)
42
Downstream targets for alpha subunit
αs: stimulation of adenylyl cyclase (AC) αi: inhibition of adenylyl cyclase (AC) αq: phospholipase activity control α12: downstream activity not known *AC makes cAMP from ATP* PDE's- phosphodiesterases
43
AC properties
AC is localized at the PM | -12 transmembrane domain and 2 catalytic domains
44
PDE
phosphodiesterases 3'5' cAMP cleaves to 5' AMP which has no signaling significance can inhibit PDE thru an increase in [cAMP]
45
cAMP
10^-7 normal concentration in the cell | decrease in concentration suppresses adenylyl cyclase/ activates PDE
46
PKA
cAMP is mediated by tetramer PKA Also called cAMP dependent protein kinase Has 2 regulatory subunits and 2 catalytic subunits In absence of cAMP, the regulatory subunits block the enzymatic activity of the catalytic subunits Binding of cAMP (cooperatively) to the regulatory subunits causes their dissociation from the catalytic subunits, allowing catalytic subunits to phosphorylate downstream substrates
47
PKA substrates
1) Phosphorylase kinase | 2) Glycogen synthase regulates transcription
48
PLCβ and Ca++ signaling
Activation of PLCβ by an alpha subunit (alpha q) causes hydrolysis of PI4,5,P2 into IP3 and DAG IP3 migrates to ER where lots of Ca++ is held IP3 opens Ca++ channels in the ER and the Ca++ rushes into the cytosol where its concentration increases To terminate signaling, an ATPase pumps Ca++ back into the ER or outside the cell
49
Calcium Calmodulin dependent kinase II
4 Ca++ binds to specific sensor calmodulin --> activation of Ca++/calmodulin dependent protein kinase --> self phosphorylation --> locked in active conformation *even if [Ca] goes down this enzyme stays active until it is dephosphorylated
50
Calmodulin
can bind up to 4 Ca++ | binding causes conformational changes
51
PKA and PKC for regulation of GPCR's
Can phosphorylate the 3rd intracellular loop and the C terminus of GPCR
52
GRK for regulation of GPCR's
g protein couple receptor kinase Ligand bound GPCRs can be phosphorylated on the C terminus by GRKs Phosphorylated receptors interact with arrestins which interfere with binding to G proteins and recruit clathrin and promote internalization of GPCRs
53
Vision
Outer segment of rods have membranes enriched in rhodopsin (receptor) bound to 11-cis retinal Exposure to light --> all-trans retinal --> conformation change in rhodopsin --> exchange of GDP to GTP in alpha subunit of transducin Free alpha subunit (alpha t) activates cGMP PDE and levels of cGMP go down cGMP gated cation channels close causing hyperpolarization --> inhibition of synaptic signaling *synaptic signaling characterized by the dark and shut off by the light*
54
Color Vision
Blue opsin: Chromosome 7 Red/green opsin: X chromosome ^recombine unequally --> explains why males more likely to be color bind
55
Smell
thousands of different olfactory GPCRs are expressed in neurons localized in the lining of the nose GPCR's coupled to g protein Golf --> subunit dissociates ----> activates adenylyl cyclase --> cAMP gated Na channels open with [cAMP] increase--> depolarization of the cell --> electrical signal is propagated into the brain
56
Taste- 5 different types
sour, salty, bitter, sweet, umami All taste receptors are coupled to the specific G protein called gustducin that activates PLCβ
57
Salty and Sour
Salt and sour do not have receptors --> mediated by H+ and Na+ ion channels
58
Sweet and Umami
Mediated by 3 GPCR's that heterodimerize into different combinations T1R1/T1R3- umami T1R2/T1R3- sweet receptors are heterogenous --> different people have different taste thresholds
59
Bitter
GPCR T2R family

MoMF (25 decks)

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