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MCBM Part 2 > Kandpal - Signal Transduction: GPCR, Enzyme Linked Receptors and Human Cancers > Flashcards

Kandpal - Signal Transduction: GPCR, Enzyme Linked Receptors and Human Cancers Flashcards

1
Q

what makes up a G-protein coupled receptor (GPCR)

A

7 transmembrane (7TM) domains, seven pass, serpentine receptors (N-terminus is extracellular and C-terminus is intracellular)

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2
Q

what are the ligands for GPCR’s

A

hormones, neurotransmitters (proteins, peptides, amino acid derivatives, and fatty acids) photon, H+, Ca2+

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3
Q

what are the 3 subunits on a GPCR

A

alpha, beta, and gamma

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4
Q

how is a G-protein activated

A

receptor protein is activated with signal molecule -> attracts GDP on alpha-subunit inactive GPCR -> phosphates GDP = GTP and alpha subunit dissociates from beta/gamma active complex

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5
Q

what controls the activity of the alpha subunit on a G-protein and how does it work

A

RGS (regulator of G-protein signaling) - acts as alpha-subunit specific GTPase activator proteins (GAPs)

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6
Q

what is the difference between stimulatory and inhibitory G-proteins

A

both are GTP bound: stimulatory activates adenylate cyclase and inhibitory inhibits adenylate cyclase

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7
Q

what is the downstream effect of an active G-protein activating adenylate cyclase

A

causes an increase in cAMP

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8
Q

what is the downstream effect of an active G-protein activating phosphodiesterase (PED)

A

decrease in cAMP -> activates protein kinases

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9
Q

what happens when a G-protein activates phospholipase C-beta

A

initiates inositol phospholipid signaling

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10
Q

how does cAMP activate protein kinase A (PKA)

A

inactive PKA (regulatory subunit + inactive catalytic subunit) -> cAMP binds to regulatory subunit and dissociates 2 active catalytic subunits - ready to phosphorylate target proteins

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11
Q

what is the target protein for PKA

A

CREB- binding protein (CBP)

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12
Q

how does PKA induce gene transcription

A

activated PKA goes into nucleus and activates CREB - both bind to CRE (cAMP response elements) on promotor region and activates gene transcription

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13
Q

what else can PKA bind to for activation (besides activating PKA)

A

CFTR: cystic fibrosis transmembrane conductance regulator = Cl- channel

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14
Q

where is phosphatidylinositol 4,5 bisphosphate (PIP2) located

A

its a minor lipid in the inner half of the plasma membrane

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15
Q

what converts PI -> PI(4)P -> PI(4,5)P2 by adding a phosphate to carbons 4 and 5

A

PI kinase

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16
Q

what converts PI(4,5)P2 to diacylglycerol and insitol 1,4,5-triphosphate

A

phospholipase C-beta (*activated by GPCR -> activated G-protein)

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17
Q

what does diacylglycerol activate

A

protein kinase C (C for calcium dependent)

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18
Q

what does insitol 1,4,5-triphosphate (IP3) do

A

binds to Ca2+ channels and releases Ca2+ from ER

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19
Q

what does the cholera toxin target

A

modifies the alpha-subunit of stimulatory G-protein (ADP ribosylation of GTP-bound alpha)

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20
Q

how does the cholera toxin work

A

the ribosylated alpha-subunit remains active and GTP cannot be hydrolyzed to GDP - adenylate cyclase is active and cAMP levels rise (CFTR remains active)

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21
Q

what are the consequences of the cholera toxin

A

diarrhea and vomiting from efflux of Cl- ions and water into gut

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22
Q

how does the Pertusis toxin work

A

modifies the GDP-bound inactive alpha-subunit and it cannot be activated to GTP - no inhibition of adenylate cyclase and cAMP remain elevated (CFTR is activated)

23
Q

what does the Pertusis toxin target

A

inhibitory G-proteins (Gi) that would normally inhibit adenylate cyclase activity

24
Q

how are G-proteins and smell related and how do they work

A

olfactory receptors have G-proteins: activated G-protein -> stimulates adenylate cyclase -> elevated levels of cAMP open gated ion channels to increase Na+ and induce action potential

25
Q

when are cGMP gated Na+ channels open in rods

A

in the dark when cGMP levels are high

26
Q

what is the activated pathway of cGMP in the rod

A

light activates rhodopsin -> 11-cis converts to all-trans -> activates transducin (Gt) -> activates cGMP phosphodiesterase (PDE) and cGMP levels fall -> closure of Na+ channels and inhibition of synaptic signaling

27
Q

what are 3 ways rods revert back to resting levels

A

all negative feedback loops: RK (rhodopsin kinase), arrestin, and RGS (regulator of G-protein signaling)

28
Q

how does RK (rhodopsin kinase) work

A

phosphorylates cytosolic tail of activated rhodopsin which then cannot activate transducin

29
Q

how does arrestin work

A

binds to phosphorylated rhodopsin = more inhibition of rhodopsin activity

30
Q

how does RGS (regulator of G-protein signaling) work

A

binds to activated transducin = GTP is converted to GDP = inactivation of transducin

31
Q

what are enzyme linked receptors responsible for

A

growth, proliferation, differentiation and survival of cells

32
Q

what are the characteristics of the receptor in enzyme linked receptors

A

transmembrane proteins that have intrinsic enzymatic activity or are associated with enzymes

33
Q

what are the ligands for receptor tyrosine kinases (PTK)

A

secreted growth factors and hormones (EGF, PDGF, FGF, HGF, insulin, IGF-1, VEGF, NGF) or membrane bound proteins (ephrins)

34
Q

what happens with receptor tyrosine kinases after a ligand binds

A

dimerization of receptor, activation of tyrosine kinase domain, phosphorylation of tyrosines on receptor and other signaling proteins or autophosphoylation - increase kinase activity and docking sites for proteins

35
Q

what 2 things bring cells together in receptor tyrosine kinases

A

a ligand and (Eph) receptors - transmembrane proteins

36
Q

what does p13 kinase do

A

mediates cell survival and cell growth (catalyzes PI -> PI3P, PI4P -> PI3,4P2, and PI4,5 bisphosphate -> PI3,4,5P3)

37
Q

what is PTEN

A

an IPE3 phosphatase = tumor supressor

38
Q

what receptors are cytokines recognized by

A

receptors that bind to JAK (janus kinases) - cross phosphorylate each other on tyrosines

39
Q

what do activated JAK (janus kinases) phosphorylate

A

STAT (signal transducers and activators of transcription) that are docked on specific phosphotyrosines on the receptor

40
Q

what are 2 mutations in 2 important classes of genes in cancer

A

proto-oncogenes and tumor repressing genes

41
Q

what is Ras

A

an oncogene that is activated in 30% of human cancers and can exist in 2 forms (active or inactive)

42
Q

what does active Ras do

A

it creates a cascade of phosphorylation reactions that relay a signal to the nucleus

43
Q

what are the 3 core kinases involved in the Ras cascade

A

MAPKKK (Raf kinase), MAPKK (Mek kinase), and MAPK (Erk kinase)

44
Q

what is ErbB: Her2/neu

A

it is amplified in breast cancers - Her2 is an epidermal growth factor receptor 2 and maps to 17q12-q21

45
Q

what is herception

A

antibody to Her2 (management of breast cancer) it stops intracellular signaling/transcription, proliferation and anti-apoptosis

46
Q

what are cell cycle regulatory proteins

A

cyclin dependent kinases (cdks) specific for G1, G1/S, S, and M phases

47
Q

what regulates cdk’s

A

cyclins D, E, A, and B (synthesized and degraded each cell cycle)

48
Q

what controls the activity of cdk’s

A

CAK, CKI and phosphatases

49
Q

what inhibits activity of cdks during cell cycle arrest

A

p21 which is regulated by p53

50
Q

which type of Rb (retinoblastoma) has tumors in one eye and is consistent with 2 random genetic hits

A

the sporadic type (familial is both eyes and has single random genetic hit)

51
Q

how does Rb (retinoblastoma) work

A

Rb is usually coupled with E2F and inhibits S-phase - tumors occur when they are not connected and E2F activates transcription

52
Q

what does p53 do

A

senses genetic damage in cell and arrests cell “guardian of genome”

53
Q

what is APC and what does it do

A

APC is mutated in tumor cells and prevents beta-catenin from binding to complex which prevents phosphorylation and degradation of catenin = promotes proliferation and transcription of tumor cells in colon cancer

54
Q

what is a wnt growth factor

A

it does the same thing as an APC by occupying a frizzled receptor

MCBM Part 2 (15 decks)

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