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Block 1 Week 1 > Introduction to Signal Transduction > Flashcards

Introduction to Signal Transduction Flashcards

1
Q

How can signals be sent? (x4)

A

1) Endocrine: secreted into blood acting on distant target (hormones)
2) Paracrine ( acting on nearby cell, neurotransmitter)
3) autocrine ( secreted ligand acting on same cell (growth factor)
4) cell to cell signaling: plasma membrane attached proteins can signal to each other to affect dilation etc

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2
Q

what is signal transduction?

A

process of converting extracellular signals into intracellular responses

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3
Q

how do cells respond to signals? (2 ways)

A

1) fast: by changing activity of existing enzymes

2) slow: change levels of expression of enzymes vis gene regulation

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4
Q

what does signal amplification mean?

A

-at each step of signal transduction pathway, the number of activated participants increases

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5
Q

What does amplification cascade mean? Example of something that has it?

A

ex= hormone signaling pathways

- one epinephrine molecule leads to 1000s of cAMP final product. each step in process results in amplification

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6
Q

rate of responses to extracellular signals?

A

1) rapid:(seconds-minutes) phosphoryaltion, ion/glucose/aa transport
2) delayed: (hours) trxn/translation
3) prolonged: (hours-days) requires trxn of cell cycle genes, cell growth/proliferation

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7
Q

How are signals conveyed in the cell?

A

1) receptor mediated

2) non-receptor mediated

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8
Q

what is receptor mediated signaling?

A
  • membrane receptors on cells respond to responsed to extracellular signals that bind to cell surface
  • allows cells to respond to hormones etc
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9
Q

How do steroids signal?

A

-use nuclear receptors that are trxn factors capable of responding directly to steroid binding

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10
Q

Non receptor mediated signaling?

A
  • cells sense contacts w/ the extracellular matrix or other cells by proteins etc
  • cells turn on internal signals in response to situations such as poorly folded proteins
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11
Q

G-protein coupled receptors (GPCR)

A
  • largest protein superfamily
  • heptahelical (7 transmembrane)
  • couples to one or two of the 20 known heterotrimeric G-proteins at one time to activate alpha subunit
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12
Q

What is a G-protein?

A
  • heterotrimeric protein (alpha, beta gamma)

- activated/deactivated by many GEFs/GAPs

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13
Q

Alpha subunit of G-protein?

A

-GTP binding trimer with Beta and gamma

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14
Q

GEF & GAP?

A

1) GEF (guanine nucleotide exchange factor) activate reactions by exchanged GDP–>GTP
2) GAP (GTPase activating protein) cause hydrolysis of GTP–>GDP therefore terminating signaling

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15
Q

GPCR/G-protein steps?

A
  1. GPCR bound by ligand, activated (G-protein bound GDP inactive state)
  2. ligand binding/ conformational changes causes GDP–>GTP hydrolysis by GEFs activating G protein
  3. G-protein alpha subunit binds GPCR, dissociation from beta gamma subunits
    a. Alpha subunit & some pieces of beta gamma cause downstream signaling
  4. Downstream signaling activates kinases which dephosphorylate GPCR causing it to dissociate from G-protein alpha subunit
  5. RGS (regulator of G protein signals) are protein kinases that cause hydrolysis of GTPGDP therefore deactivating the G protein
    a. GTP hydrolysis is the internal clock, controls G protein signaling
  6. GPCR ONLY ACTIVE WHEN BOUND TO GPROTEIN no enzymatic activity on own
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16
Q

G alpha protein subunit?

A
  • are G proteins
  • 21 different versions encoded in human genome
  • activated by different GPCRs, regulate variety of diff effector proteins that synthesize second messengers
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17
Q

cAMP and G alpha proteins?

A
  • cAMP is a second messenger
  • has stimulatory G alpha subunit activates it
  • an inhibitory Galphai inhibits production
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18
Q

G(alpha)s

A

alpha–> adenylate cyclase (AC)–> cAMP–> protein kinase A (PKA)

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19
Q

G(alpha)i

A

alpha inhibits AC-> lower cAMP production

-actiavtes RhoGEFs & K+ channels

20
Q

G(Alph)q

A

1) couples to phospholipase CB (PLCB) to hydrolyze PIP2 & produce inositol triphosphate (IPS) and diacylglycerol (DAG)
2) IP3 mobilizes Ca2+
3) DAG and Ca2+ activate PKC

-can activate RhoGEfs & K+ channels

21
Q

G(alpha) 12/13

A

-couples to certain RhoGEfs to activate RhoA, PlC

22
Q

Typical G(alpha)s signaling?

A

1) binds AC which, converts ATP–>cAMP, cAMP activates PKA

2) can activate K+ & Ca2+ channels

23
Q

How cAMP made/deactivated?

A

1) made by conversion of ATP–>cAMP via Adenylate Cyclase

2) degraded by PDE (phosphodiesterase)

24
Q

Typical G(alpha)I signaling?

A

1) inhibits AC, therefore inhibits cAMP production & PKA production
2) beta & gamma subunits can activate RAS

25
Q

Typical G(alpha)q signaling?

A

1) couples to PLC(beta)
2) hydrolyzes PIP2
3) PIP2 makes DAG + IP3 which move calcium 4) DAG & Ca2+ activate PKC

26
Q

What are Receptor Tyrosine Kinases?

A
  • growth factor receptors
  • 6 families
  • some have intrinsic kinase activity
  • some have kinase activity only after dimerization (growth factor families)
  • cell surface receptors w/ into and extra cellular domains
27
Q

intrinsic kinase activity?

A

insulin family

-is dimeric

28
Q

How activate Receptor TK?

A

1) ligand binds extracellular domain, conformational change(dimerization) or autophosphoryaltion if is an intrinsic tyrosine kinase
2) RTK-P Phosphorylated sites recruit binding/adapter proteins
3) Proteins activated: Protein kinases, lipid kinases, Monomeric G protein

29
Q

kinase activity only after dimerization?

A

-growth factor families: EGFR, PDGFR, FGFR

30
Q

Extra cellular domain structure vs intracellular domain RTK?

A

extra: similar to IgG, fibronectin or cysteine rich repeats
intra: conserved w/ single tyrosine kinase domain or 2 tyrosine kinase repeats

31
Q

Monomeric GTPases?

A
  • Ras
  • molecular switches for cell division, growth, gene expression
  • are downstream of membrane receptors; bind & activate other proteins in signaling cascade
32
Q

How are GEF’s activated?

A

1) y phosphorylation

2) active Tyrosine Kinase association

33
Q

What is RAS-GEF called?

A

SOS

34
Q

How monomeric GTPases (Ras) activated/deactivated? Where located?

A
  • activated by exchange of GTP for GDP by GEFs
  • deactived by GTP hydrolysis (Gap) which acts as intrinsic timer

2)RAS attach to membrane via farnesyl & myristoylation

35
Q

ERK1/2 Cascade? (5 steps)

A

1) RAS activated by GTP, farnesylation RAF brings RAF to active RAS membrane. Phosphorylate it
2) Active RAF (MAPKKK) looses auto inhibition
3) RAF phosphorylates MEK1/2 (MAPKK) activating it
4) MAPKK (MEK1/2) phosphyrlates & activates ERK1/2
5) ERK1/2 phosphorylated can enter nucleus and effect early trxn factors that promote cell proliferation

36
Q

What does the ERk1/2 cascade link?

A

Links external cues from the RTKs to internal processes (Ras) down to cell proliferation

37
Q

PI3Kinase?

A
  • is a lipid kinase that promotes cell survival, migration & glucose uptake
  • alternative to RAS/RAF pathway
38
Q

PI3 Kinase mechanism?

A

1) activated by RTK & GPCR
2) converts membrane lipids PIP2–> PIP3
3) PIP3 attracts proteins containing PH-domains

39
Q

Downstream effects of PI3-Kinase?

A

1) Akt (protein kinase B)
^IMPORTANT
2)RhoA family GTPases
3) Glut 4

40
Q

Examples of cellular oncogenes? How do they work?

A

1) src
2) Raf
3) Ras
4) Myc
* induce proliferation
- act on the mitogen activated protein kinase (MAPK) pathway

41
Q

Akt?

A
  • downstream effector of PI3 Kinase
  • is a protein kinase B (ser-thre kinase)
  • involved in mitogenic proliferation & survival
42
Q

Jak/STAT pathway?

A
  • JAK Family (Janus Kinase) = 3 JAK isoforms & tyrosine kinase 2 (TYK2)
  • JAK inhibitors used to treat autoimmune diseases
43
Q

Jak/stat pathway?

A

1) interferon ligand binds receptor, cytosolic cross phosphorylation of receptor
2) activates JAK, which phosphorylates tyrosine kinase
3) binding proteins activated by JAK phosphorylation become TF (Stats_ enter nucleus and effect immunity/inflammation gene

44
Q

Non-receptor Tyrosine Kinases?

A
  • some tyrosine kinases don’t have extracellular/membrane domains
  • post translation modification allow them to attach to membrane
  • unlike receptor TKs, intracellular domains are highly variable
  • src=example
45
Q

src?

A

1) first non-recepeptor tyrosine kinases
2) membrane localization =myristoylation
3) regulation= autoinhibition that suppresses kinase domain
4) phosphorylates: EGFR & cytosolic proteins
5) function: trxn cell cycle genes, proliferation, cell rounding

OVEREXPRESSED IN CANCER

Block 1 Week 1 (9 decks)

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