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Biochem Exam 3 > RTKs & GPCRs > Flashcards

RTKs & GPCRs Flashcards

1
Q

RTK structure

A

receptor tyrosine kinase

  • extracellular ligand binding domain
  • single pass transmembrane domain
  • intracellular kinase domaine
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2
Q

RTK role

A
  • couple ligand binding (growth factors) to downstream signaling + gene transcription
  • all receptors (except for insulin) control rate of cell proliferation and grown
  • insulin receptor controls glucose homeostasis
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3
Q

RTK ligands

A
  • act as dimers: PGDF, fibroblast GF, VEGF (vascular endothelial), NGF (nerve), m-CSF (colony), IGF-1, insulin
  • acts as a monomer: EGF
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4
Q

RTK signaling (key events)

A
  • receptor dimerization through ligand binding, increases receptor’s affinity for one another, brings close together
  • receptor dimerization allows intracellular tyrosine kinase domains to cross phosphorylate on tyrosine residues
  • signaling proteins have domains (4) that recognize P-Try (phosphotyrosine)
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5
Q

SH2 domains

A

recognize P-Tyr + 2AAs on C-terminus

-contains 3 binding pockets

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6
Q

PTB domains

A

recognize P-Tyr + 2-3AAs at N-term

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7
Q

SH3 domains

A

recognize and bind to proline (AA) rich sequences

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8
Q

PH domains

A

recognize phospholipids

i.e. phosphotidylinositol bi + tri phosphates, PIP3, PI3

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9
Q

proteins with SH2 domains

A

GRB2
p85 (PI3K, 2x)
PLC gamma (2x)
STAT

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10
Q

proteins with SH3 domains

A

GRB2 (MAPK, 2x)

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11
Q

MAPK pathway (first step)

A

mitogen activated protein kinase

-upon ligand binding, the receptor dimerizes, cross phosphorylation of tyrosine residues (have Ras anchored 2x nearby)

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12
Q

GEF

A

GDP/GTP exchange factor

  • protein cofactor
  • may inactivate or activate a protein, etc.
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13
Q

Ras - structure

A

only PM-bound Ras involved in signaling. covalent attachment of hydrophobic anchors

  1. enzyme attaches hydrophobic farnesyl residue at a C-term cysteine residue on Ras, attaching to PM
  2. (in many Ras isoforms) second hydrobic anchor, a fatty acid residue covalently binds to a different C-term cys residue
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14
Q

Ras - structure

A

only PM-bound Ras involved in signaling. covalent attachment of hydrophobic anchors

  1. enzyme attaches hydrophobic farnesyl residue at a C-term cysteine residue on Ras, attaching to PM
  2. (in many Ras isoforms) second hydrobic anchor, a fatty acid residue covalently binds to a different C-term cys residue
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15
Q

MAPK - GRB2

A

protein that binds to phosphotyrosine
SH3-SH2-SH3
-SH2 domain binds to P-Tyr

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16
Q

MAPK - SOS

A

SOS protein recruited to PM

  • can bind to SH3 domain on GRB2
  • is a Ras-GEF
  • since Ras is nearby, can exchange GDP –> GTP
17
Q

MAPK - Ras

A

-Ras-GTP, activated by SOS can bind Raf

18
Q

MAPK - Ras

A

-Ras-GTP, activated by SOS can bind nearby Raf

19
Q

MAPK - Raf

A
  • is activated by binding of Raf to Ras-GTP paired with other activity in PM
  • serine/threonine protein kinase
  • once activated, can phosphorylate, and activate MEK
20
Q

MAPK - MEK

A
  • phosphorylated/activated by active Raf
  • protein kinase
  • MEK-Pcan phosphorylate/activate ERK
21
Q

MAPK - ERK

A

extracellular regulated kinase
ERK-P dimerizes
-travels to nucleus to phosphorylate/activate transcription factors related to cell proliferation
-cytoplasmic targets

22
Q

inactivation of MAPK pathway (4)

A
  1. spontaneous hydrolysis of GTP to GDP, inactivates Ras
  2. Ras-GAP hydrolyzes Ras-GTP
  3. protein phosphatases (tyr and tyr/ser) dephosphorylate + deactivate every component of the signaling pathway
  4. internalization of RTK via clathrin-mediated endocytosis
23
Q

overview of MAPK pathway

A

RTK –> YP –> GRB2 (SH2) –> SOS (recog SH3, Ras-GEF) –> Ras-GTP –> Raf (ser/thr k) –> MEK-P (pk) –> ERK-P + ERK-P –> cytoplasmic/nuclear targets

24
Q

PIP3

A

phosphotidyl inositol-3,4,5-triphosphate

-PI is pat of every PM, each hydroxyl can by phosphorylated by a specific lipid kinase

25
Q

PI3K - structure

A
  • family of lipid kinases, phosphorylate PI at C3 OH
  • PIP3k Type A: two subunits
    1. p85: regulatory, has 2SH2 domains
    2. p110: catalytic, binds Ras-GTP
    inactive: p85 binds to p110, blocks kinase activity
26
Q

PI3K signaling pathway

A
  1. RTK activation
  2. p85’s SH2 domains bind 2 P-Tyr on RTK
    p85 no longer bound to p110
  3. p110 can bind to Ras-GTP (GRB2, SOS), now fully active
  4. PI3K can phosphorylate PI-4,5-P2 at C3 hydroxyl
  5. increased levels of PIP3 in PM
27
Q

Akt (PKB) - structure

A

contains PH and kinase domains

  • with low [PIP3] in PM, the PH domain is bound to the kinase domain, inhibiting its enzyme activity. protein not bound to PM
  • with high [PIP3] in PM, recruited to PM
28
Q

Akt pathway

A

PDK-1 (PI dependent k -1)and Akt are serine/threonine kinases

  • when [PIP3] in PM increases, they’re recruited to the PM by their PH domains. both bind to PIP3, close proximity
  • full Akt activation requires two phosphorylations
    1. PDK-1 phosphorylates Akt on threonine residue at the activation loop of its kinase domain
    2. mTORC2: phosphorylates Akt on a hydrophobic serine residue
29
Q

Roles of Akt (3)

A
  1. anti-apoptotic
  2. glucose metabolism/ energy homeostasis
  3. target of mTORC1
30
Q

TOR

A

(target of rapamycin, natural biological activator)

  • serine/threonine kinase
  • TORC1 + TORC2, bound to different regulatory proteins
  • mTORC1: regulated by GF, increases cell growth through inc protein synthesis. inhibited by rapamycin.
    • binds and is activated by Rheb-GTP
  • mTORC2: phosphorylates/activates Akt. resistant to rapamycin.
31
Q

Rheb

A

(Ras homologue enriched in brain, but ubiquitous)

  • GTPase
  • no Rheb-GEF
  • Rheb-GAP is TSC1/2
32
Q

TSC1/2

A

-active TSC1/2 complex is a GAP for Rheb, inactivating it (Rheb-GTP to -GDP)
-active Akt (ser/thr k) + ERK-P phosphorylate + inhibit TSC2, thereby inhibiting its Rheb-GAP function
-with a build up of Rheb-GTP, have increased levels of activated mTORC1 leading to increasing protein synthesis and cell proliferation
[Akt phos/inactivates the inhibitor (TSC1/2), thus activated mTORC1]

33
Q

tuberus sclerosis complex

A
  • hyperactive mTORC1 (mutation in TSC1/2, no GAP activity)
  • increased protein synthesis, increased cell size
  • but MAPK not affected by mutation, so no matching increased in cell proliferation
  • leads to tumors/giant cells
34
Q

termination of PI3K/Akt pathways (2)

A

tumor suppressing enzymes (protein and lipid phosphatases) act to decrease PIP3 in PM

  • p10: desphosphorylates C3 in PIP3
  • Ship2: desphosphorylates C5 in PIP3

-mutation in PI3K or Akt pathway can lead to tumors

35
Q

PLCy (gamma) pathway

A

(PI4K and PI5K always present, have PIP2 in PM)
PLCgamma has two SH2 domains + PH domain
-SH2 domains, can bind to active RTK, which then phosphorylates + activates PLCgamma
-PLCgamma cleaves PIP2 in PM to IP3 and DAG
-DAG remains associated with PM w/ 2 FA chains
-IP3 travels to ER, opens Ca2+ channels, inc Ca2+ in cytoplasm
-w/ Ca2+ DAG

36
Q

proteins with PH domains

A

PI3K
Akt (PKB)
PDK-1
PLC gamma

37
Q

RTKs + cancer

A

-ErbB Receptors (erythroblastosis oncogene B)
breast cancer, 25% gene amp/overexp of Erb2 (Her2)
-N term trunctation can lead to dimerization and activation of receptor in absence of ligand
-can design mAbs for EC portion of receptor
-can inhibit kinase domain

38
Q

JAK/STAT

A
  • receptor binding causes dimerization, but may not have intrinsic tyrosine kinase activity
  • recruits soluble JAK (dimerized). binds, cross phos on tyr residues of itself + receptor
  • phos-tyr residues of receptor recognized by SH2 domains on STAT proteins (signal transducers and activators of transcription)
  • STAT binds + is phosphorylated by JAK
  • STAT can dimerize, dissociate and travel to nucleus

Biochem Exam 3 (1 decks)

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