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MCG > LEC5-8: Signal Transduction > Flashcards

LEC5-8: Signal Transduction Flashcards

1
Q

what is signal transduction

A

process by which cells receive & respond to cues from biological environment

essentialy for normal development, homeostatis

if wrong/aberrations, get disease like: cancer, ID, developmental genetic aberration, psychiatric disease, diabetes

target for most drugs = signal transduction

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2
Q

general categories of cell-cell signaling? how do they differ?

A

1) endocrine: cell produces hormone, it enters into circulation, travels long distance > target cell; i.e. pituitary-synthesized hormone
2) paracrine: signaling cell releases factor into local area; ddoesn’t enter bloodstream; i.e. SHH
3) neuronal: specialized paracrine signaling w/ neutrotransmitters
4) contact-dependent: action limited to cell adjacent, cells must be in contact to hit target cell
5) autocrine: cell both makes signaling factor & responds to it; i.e. cancer cells

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3
Q

types of signaling factors?

A

proteins

peptides

amino acids/their derivatives

lipids

prescription drugs

drugs of abuse

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4
Q

what is the basic principle of cell-surface receptors?

A

high affinity btwn hydrophilic signal molecule & cell-surface receptor makes them bind

causes signal trasnduction event w/in cell; just diffusion wouldn’t work

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5
Q

describe process of FAST signaling

what does it cause?

A

extracellular signal molecule > cell-surface receptor protein > intracellular signaling pathway > altered protein function > altered cytoplasmic machinery > altered cell behavior

< sec to mins

occurs in CYTOPLASM only

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6
Q

describe process of SLOW signaling

what does it cause?

A

extracellular signal molecule > cell-surface receptor protein > nucleus > altered protein synthesis by changing transcriptional program > altered cytoplasmic machinery > altered cell behavior

SLOW: mins to hrs

occurs in both CYTOPLASM and NUCLEUS

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7
Q

major classes of cell surface receptors?

A

1) G-protein coupled receptors (GPCRs)
2) Receptor tyrosine kinases (RTKs)
3) Cytokine receptors

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8
Q

what transmits through GPCRs (what are the LIGANDS)?

A

neurotransmitters (epinephrine, serotonin, dopamine)

histamine

sensory stimuli (light, odorants)

many prescription drugs

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9
Q

what is the structure of the GPCR?

how does it basically work?

A

protein w/ 7 transmembrane domains

ligand binds the receptor extracellularly, causing conformational change in the receptor

change allows intracellular domain to interact w/ heterotrimeric G protein

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10
Q

what is the structure of the heterotrimeric G protein?

what is each subunit able to do?

A

has 3 subunits: alpha, beta, gamma

beta-gamma are always found together

alpha is able to bind GT & to hydrolyze bound GTP to GDP

alpha and gamma have post-translational fatty acid residue connected - can insert into inner surface of plasma membrane

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11
Q

describe activation pathway of the G protein

A

1) heterotrimeric G protein is inactive when bound to GDP, all 3 subunits are interacting then
2) ligand binds GPCR > receptor changes conformation to allow interaction w/ alpha subunit of G protein
3) alpha subunit releases GDP, binds GTP
4) alpha subunit w/ GTP dissociates from beta-gamma subunit
5) alpha-GTP and beta-gamma subunits now interact w/ downstream receptors

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12
Q

what causes alpha subunit of G protein to switch GDP for GTP when activating?

A

nucleotide exchange:

[GTP] > [GDP] in cytoplasm

so, if GDP is expelled, GTP replaces it

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13
Q

describe the pathway for inactivation of the G protein

A

1) after activating its target protein, alpha subunit hydrolyzes GTP to GDP, with aid of an RGS, regulatory of G-protein signaling
2) **GDP-bound alpha subunit is inactive **
3) inactive alpha subunit re-associates w/ beta-gamma subunit b/c GDP-alpha has affinity for beta-gamma subunit

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14
Q

what is RGS? what is its function?

A

membrane-bound regulatory of G protein signaling protein

increases GTP-ase activity of alpha subunit of heterotrimeric G-protein, allows it to inactivate and “reset” much faster

aka helps alpha subunit hydrolyze GTP to GDP

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15
Q

how many GPCRs are there, and how many different alpha/beta/gamma subunits?

A

1000 GPCRs, 25 alpha/beta/gamma subunits

so many different GPCRs will work thru similar pathways to the subunits

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16
Q

what are small or secondary messengers?

A

a non-protein/enzyme intermediate molecule that acts as an intermediate to propagate a signal from a receptor

i.e. adenylyl cyclase, cAMP, IP3, DAG, Ca

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17
Q

what are the 3 classes of G-protein’s alpha subunits, what do they directly do?

A

Gs: activates adenylyl cyclase

GI: inactivates adenylyl cyclase

Gq: activates phospholipase C

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18
Q

describe the pathway of GS on its downstream targets

A

1) activated G-alpha-S activates adenylyl cyclase
2) adenylyl cyclase converts ATP to cAMP
3) cAMP activates targets, like PKA
4) cAMP binding to PKA activates it by dissociating its regulatory subunits
5) PKA phosphorylates targets, i.e. glycogen phosphorylase & glycogen synthase

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19
Q

what is a kinase? what is a protein kinase?

A

kinase: enzyme that phosphorylates, usually from ATP to a substrate

protein kinase: enzyme in which substrate is a protein

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20
Q

what are the 2 major types of protein kinases?

A

1) kinases that phosphorylate Ser/Thr residues
2) kinases that phosthorylate Tyr residues

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21
Q

what is the structure of PKA?

how is it activated?

A

PKA has 4 subunits: 2 regulatory, 2 catalytic

when cAMP binds to the 2 regulatory subunits, they no longer have affinity for catalytic subunits

catalytic subunits go forward & phosphorylate substrates, propagate signal

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22
Q

describe pathway involving adrenaline and GS

what is the result? and what kind of response is this?

A

1) situation of fight/flight, adrenaline binds GPCR, activates GS
2) GS binds & activates adenylyl cyclase
3) adenylyl cyclase converts ATP to cAMP
4) cAMP activates PKA
5) PKA phosphorylates & activates phosphorylase kinase
6) phosphorylase kinase phosphorylates phosphorylate glycogen by hydrolyzing ATP to ADP
7) phosphorylated phosphorylate glycogen causes glycogen breakdown

this gives your muscles energy to run!

FAST signaling!

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23
Q

what steps in the GS/adrenaline pathway are sites of amplification? which are not sites of amplification?

A

Amplification sites (>1:1 ratio of activator>activated):

adenylyl cyclase activates cAMP

PKA phosphorylates substrates

Not amplification sites (1:1 ratio of activator>activated)

GS activates adenylyl cyclase

cAMP activates PKA

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24
Q

what is meant by a site of amplification?

A

signaling such that limited amount of information input causes explosive burst of information output

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25
Q

what is signal branching? example?

A

when 1 receptor protein can activate more than 1 kind of G protein

i.e. PKA has numerous substrates

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26
Q

why are signal transduction pathways reversible? what are examples of this?

A

because if signaling goes awry, that can result in disease

1) alpha subunit + RGS cause GTP hydrolysis to GDP
2) cAMP phosphodiesterase digests cAMP to AMP, which is a biologically inert signaling molecule
3) protein phosphotases inactivate substrates that require phosphate for activation

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27
Q

describe the phospholipase C / Gq pathway

A

1) signal molecule activates its GPCR
2) Gq subunit of G protein binds & activates phospholipase C-beta
3) phospholipase C breaks down the membrane phospholipid PIP2 into IP3 and DAG
4) IP3 can activate release of Ca2+ inside the cell, which activates PKC, which causes other signaling functions

DAG directly activates PKC also

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28
Q

what are IP3 and DAG examples of?

A

secondary messengers!

from the phospholipase C pathway

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29
Q

what is the function of Gi?

A

inhibits adenylyl cyclase

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30
Q

describe activation and pathway of Gt

A

1) rhodopsin receptor activates Gt
2) Gt activates cGMP phosphodiesterase
3) cGMP phosphodiesterase breaks down cGMP

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31
Q

describe pathway of cholera toxin

A

1) cholera toxin is an enzyme. it ADP-ribosylates GS-alpha
2) ADP-ribosylated GScannot hydrolyze GTP to GDP now
3) GSw/ GTP thus remains permanently activated, keeps **activating adenylyl cyclase **
4) activated adenylyl cyclase increases cAMP levels, activates PKA
5) prolonged PKA activation in intestinal epithelium causes efflux of Cl- and water into gut

causes copious, watery diarrhea

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32
Q

describe pathway of pertussis toxin

A

1) pertussis toxin ADP-ribosylates alpha-subnit of Gi
2) prevents Gi from binding to GPCRs

this inhibits the inhibitor

3) leads to increased [cAMP]

causes bacteria colonization, leads to whooping cough

33
Q

what are 3 ways in which the GPCR to PKA can be shut down?

A

1) Gi activation, as it inhibits adenylyl cyclase, which activates cAMP which activates PKA
2) Block Gs from activating adenylyl cyclase
3) Block cAMP, as that is what adenylyl cyclase activates, and cAMP then activates PKA

34
Q

what is the generalized structure of an enzyme-coupled receptor?

A
  • receptor with extracellular ligand-binding, membrane-spanning, and intracellular regions
  • receptors are **dimerized **(brought together) by ligand binding
  • receptors may be homodimers (same protein) or heterodimers (different proteins)
  • enzyme activity may be intrinsic to receptor, or intracellular region may bind to receptor non-covalently
35
Q

what is the largest family of enzyme-coupled receptors?

what is its structure?

A

receptor tyrosine kinases

extracellular: ligand-binding domain

single membrane spanning region

intracellular: tyrosine-kinase domain

36
Q

ligands of receptor tyrosine kinases (RTKs)?

A

platelet-derived growth factor

epidermal growth factor

fibroblast growth factor

insulin

37
Q

describe signal transuction for receptor tyrosine kinases (RTKs)

A

RTKs exist as very weakly inactive in plasma membrane

1) ligand binds RTK

**RTK dimerizes **

2) dimerization causes receptors to be phosphorylated (auto or trans)

1st: phosphorylation of tyrosine-kinase domain

2nd: phosphorylation outside of tyrosine-kinase domain

receptors are now active

3) phosphates provide binding sites for next factors in signal cascade, and activates receptor’s catalytic function

38
Q

what are the classic domains of RTK signaling?

what does each bind?

A

SH2: binds phosphotyrosine regions

SH3: binds polyproline regions

specific factors’ SH2 or SH3 domains bind to phosphate of specific Tyr residues

39
Q

what are examples of modular enzymes?

what’s their function?

A

modular enzymes: contain SH2 and SH3 domains + an enzymatic component

PLC-gamma: binds to RTKs

PLC-beta: binds GQ of G-protein alpha subunit

40
Q

what are modular adaptor proteins? their function?

A

modular signaling protein with SH2 and SH3 domains but NO ENZYMATIC activity

i.e. Grb2

41
Q

what is Ras?

when is it active/inactive?

how does it switch from active to inactive state?

A

Ras: s small G-protein which can bind GTP and GDP, has GTPase activity

when GTP-bound: active; GDP-bound: inactive

when signal enters, GEF (guanine nucleotide exchange factor) converts GDP to GTP, which turns Ras ON

Ras needs a GAP (GTPase activating factor) to hydrolyze GTP to GDP, turns Ras OFF

42
Q

describe how the MAP kinase cascade becomes activated via Ras

A

1) prior to signaling, **Grb and SOS are bound **
2) when RTK activated by a ligand, generates a phosphotyrosine residue
3) Grb2 recognizes this residue, and **Grb2 activates **
4) Grb2 recruits SOS
5) SOS causes Ras nucleotide exchange of GDP for GTP

Ras becomes activated

43
Q

what activates the MAP cascade?

A

Ras

44
Q

describe the MAP kinase cascade

A

growth factor binds from extracellular space

1) when RTK is phosphorylated, Grb2 binds to it via SH2 domain (phospho-tyrosine binding)

SOS is constituitively bound to Grb2 via its SH3 domain (which recognizes proline-rich area of Grb2)

2) SOS activates Ras
3) Ras activates Raf (MAPKKK)
4) Raf phosphorylates MEK (MAPKK)
5) MEK phosphorylates ERK (MAPK)

causes changes in protein activity and changes in gene expression

45
Q

what is the relationship between factors of the MAP pathway and cancer?

A

MAP is a major pathway that’s deregulated in cancer

RTK may be multiplied or amplified

Ras is activated by point mutations, most commonly mutated oncogen in cancers

Raf sometimes also activated- esp in melanomas

46
Q

what is herceptin?

A

breast cancer drug

is antibody against a specific RTK that’s innappropriately active in breast cancer, so interferes w/ MAP pathway

47
Q

describe the PI-3 kinase pathway

A

1) PI-3K is a complex of a regulatory subunit, p85, and catalytic subunit, p110
2) p85 has SH2 domain that binds activated RTKs, allows access of p110 to PIP and PIP<strong>2</strong>
3) PI-3k phosphorylates PIP and PIP2 on 3-position of inositol ring (= PIP3)
4) PIP3 activate Akt, a ser/thr kinase
5) activated Akt phosphorylates substrates that promote cell survival & inhibit apoptosis

48
Q

what is PTEN’s function?

A

tumor suppressor gene

removes phosphate from 3-position of phosphoinotides (PI3)

if mutated, the PI-3K pathway will not be turned off, and cell survival continues > tumors

49
Q

what are common causes of human cancer caused by mutations in RTK pathways?

A

1) mutations in RTKs, mutations in Ras, muations in BRaf (a type of Raf) **drive pathway activation **in absence of growth factors
2) mutations leading to constitutive activation of **PI-3K **pathway, b/c promotes cell survival

50
Q

what are some similarities & differences between GPCRs and RTKs?

A

BOTH: interact thru phospholipase C

only GPCRs: turn on adenylyl cyclase

only RTKs: turn on MAP kinase, Akt kinase pathways

51
Q

what are ligands of cytokine receptors?

A

prolactin, growth hormone, interferons, erythropoietin

52
Q

what is similar/different btwn RTKs and Cytokine Receptors?

A

RTK: single polypeptide

BOTH RTK and Cytokine extracellular portion: amino terminus, binds ligands

RTK intracellular portion: carboxy terminus, intrinsic tyrosine kinase activity

Cytokine receptor intracellular portion: carboxy terminus, DOES NOT have intrinsic tyroskin kinase activity, or any other catalytic activity; non-covalently binds non-receptor tyrosine kinase that has intrinsic tyrosine kinase activity, JAK proteins

53
Q

what are JAK proteins?

A

non-receptor tyrosine kinases associated w/ the intracellular portion of cytokine receptors

when complexes with cytokine receptor, allows cytokine receptor to behave like RTKs in that they undergo ligand-induced dimerization

54
Q

describe the cytokine receptors/JAK protein complexes signal pathway

A

1) prolactin/interferons/growth hormone binds cytokine receptor/JAK complex extracellularly
2) cytokine receptor/JAK complex undergoes dimerization, cross-phosphorylation, activation of JAK proteins
3) JAK proteins phosphorylate intracellular portion of cytokine receptor
4) SH2-containg proteins bind to cytokine receptor

55
Q

what proteins bind to activated cytokine receptor?

what does binding cause? describe pathway

A

SH2-containing proteins: STAT (signal transducer and activator of transcription), are transcription factors

1) activated cytokine receptors phosphorylate STAT
2) receptors dimerize when pY of one STAT binds SH2 of its dimeric partner & vice versa
3) dimerized STATs translocate to nucleus, bind to DNA, activate gene expression

56
Q

what are the ligands of receptor serine/threonine kinases?

A

only ligands of the TGF (transforming growth factor)-beta/BMP (bone morphogenetic protein) family

57
Q

what is the structure of receptor serine/threonine kinases?

A

heterodimers

Type I and Type II

both are single-pass transmembrane proteins; have extracellular ligand binding domain, intracellular ser/thr kinase domain

58
Q

function of TGFbeta/BMP proteins?

A

embryonic development, wound healing, disease-related fibrosis, cancer

59
Q

describe the signal transduction pathway for TGFbeta/BMP on receptor tyrosine kinases

A

1) TGFbeta ligands induce Type I and II receptors to dimerize
2) Type II receptors are constituitively active

Type II receptors phosphorylate Type I receptors

3) Type I receptor kinase activity activates

Type I receptors phosphorylate SMAD factors

4) phosphorylated R-SMADs dimerize with co-SMADs (non-phosphorylated)
5) R-SMAD/co-SMAD dimer enters nucleus, induces expression of specific genes

60
Q

how is the Notch signal activated?

A

when a Delta or Jagged-expressing cell comes into direct physical contact w/ a Notch-expresing cell

example of contact-dependent signaling

61
Q

what is unique about R-Smads?

A

they are a target for many kinases, so for other pathways beyond the TGF-beta/BMP signaling pathway

62
Q

describe Notch pathway

A

1) Notch is bound by its ligand, Delta or Jagged

intracellular domain is proteolytically cleaved

2) Cleaved Notch intracellular domain (NICD) enters nucleus, interacts w/ DNA-binding factor, CSL

CSL usually inhibits Notch pathway target genes’ expression

3) CSL interaction w/ NICD makes it bind w/ transcriptional co-activators, turns on expression of notch-responsive target genes

signaling also decreases Delta expression - like on/off switch

63
Q

what kind of interaction does notch signaling demonstrate?

A

1) lateral inhibition
2) note that no amplification occurs - so need NICD to go to nucleus to have transcription activation

64
Q

what are Wnt ligands?

A

large family of secreted proteins that have a covalently attached fatty acid

65
Q

what is receptor for Wnt ligands?

describe structure of each

A

canonical complex of Frizzled & LRP5/6

Frizzled: 7 TM domains, bind Wnts via large extracellular N-terminus

66
Q

describe canonical Wnt signaling pathway without Wnt signal

A

If Wnt is inactive:

B-cateninin undergoes proteolytic destruction by APC complex

APC, axin, Ck1, GSK3-beta make up complex

CK1 and GSK3-beta, ser/thr kinases, phosphorylate B-catenin, target it for proteolytic degradation by ubiquitin proteosome system

in this state, in nucleus, TCF/LEF, DNA-binding factor, inhibits expression of Wnt pathway target genes

67
Q

describe the ways that Wnt signal pathway is maintained as off

A

when Wnt is off,

1) TCF/LEF complex binds to DNA in nucleus, inhibits txn factors from binding and expressing Wnt-related genes
2) B-catenin undergoes constant degradation

68
Q

describe pathway of Wnt signaling in the **presence **of Wnt ligand

A

1) Wnt binds Frizzled-LRP5/6 receptor complex
2) axin then binds to LRP5/6, disrupting the APC complex

Dvl binds Frizzled, leads to inhibition of CK1 and GSK3-beta, they cannot phosphorylate B-catenin

3) B-catenin thus no longer exists in phosphorylated state, is stabilized
4) B-catenin migrates to nucleus, interacts w/ TCF/LEF and txn co-activators

activates expression of Wnt pathway target genes

P3000 and CBP act as transcriptional co-activators for Wnt

69
Q

what is B-catenin’s function, outside of Wnt pathway?

A

cadherins:

B-catenin binds intracellular region of cell-cell adhesion molecules, tethers them to actin cytoskeleton, providng stability to cell-cell junctions

keeps epithelia of epithelial cells together

central area of B-cateinin protein is where binding occurs

70
Q

what does Wnt pathway regulate re: disease?

A

1) important in embryonic development
2) regulates stem cells in homeostatic maintenance of adult tissues
3) involved in cancer, esp colorectal cancer

71
Q

describe how muations in Wnt pathway lead to polops in colon (familial adenomatous polyposis / adenomatous polyposis coli)

A

APC mutations means B-catenin is always produced, never degraded

pathway is locked ON

stem cells over-proliferate, develop polops in epithelial lining of gut b/c it’s constantly regenerating

thus APC = tumor suppressor gene, B-catenin=proto-oncogene

72
Q

what is the structure of Hedgehog ligands (HH)?

A

full-length protein has N-terminal signaling domain, C-terminal auto-processing domain

C-terminal domain catalyzes proteolysis of itself into N- and C-terminal halves & simultaneously attaches a cholesterol molecuel to the new C-terminis of the N-terminal signaling domain

signaling domain then has fatty acid molecule covalently added to its N-temrinus, results in **mature, dually lipidated HH ligand **

73
Q

what is primary HH receptor?

A

Ptch1, patched; 12 TM protein

74
Q

describe signal transduction of Hedgehog in **absence **of HH ligand

A

1) Ptch1 inhibits signaling activity of Smo, another plasma membrane protein
2) If no Smo signaling, Gli, txn factor, is phosphorylated by PKA, CK1, GSK3-beta, Gli is thus proteolytically cleaved into GliR, repressor form
3) GliR enters nucleus, inhibits HH pathway target gene expression

75
Q

describe signal transduction of Hedgehog in **presence **of HH ligand

A

1) HH binds Ptch1, relieves Ptch1-mediated inhibition of Smo
2) Smo signals to prevent phosphorylation & proteolytic cleavage of Gli
3) Full-length, activated Gli protein (GliA) enters nucleus, activates expression of HH pathway target genes

76
Q

what makes the Hedgehog pathway so unique?

A

Ptch1 is actively inhibiting Smo without the binding of any ligand

this is v different from GPCR or RTK pathways

77
Q

what is significant about relationship between the primary cilium and HH signaling?

A

primary cilium is microtubule-based organelle, present on almost all cell types

HH signaling requires the primary cilium, most components of HH pathway localize to the primary cilium: Ptch1 is found there, Gli proteolytic cleave to GliR occurs there

In HH presence, Ptch1 exits the cilium, Smo enteres the cilium, Gli cleave stops, leading to GliA formation

78
Q

what is Gorlin syndrome, what is its cause?

A

basal nevus syndrome

mutations in Ptch1 result in Smo signlaling, leads to constituitive HH signaling

Causes Gorlin syndrome, which causes basal cell carcinoma of skin/medulloblastoma

Ptch1 = tumor suppressor gene, then!

79
Q

what do mutations in Sonic hedgehog cause?

A

holonprosencephaly - birth defect include cyclopia or embryonic death

cyclopamine, chemical that binds and inhibits Smo, involved

MCG (77 decks)

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