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EOM Test 3 > Cell Signaling 2 > Flashcards

Cell Signaling 2 Flashcards

1
Q

What are receptor tyrosine kinases?

A

Transmembrane cell surface receptors that possess tyrosine kinase activity in their cytoplasmic domain

Most are single-chain polypeptides that exist as monomers in the absence of ligand binding

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2
Q

What is each receptor tyrosine kinase monomer composed of?

A

Extracellular binding domain

Transmembrane a-helix

Cytoplasmic domain with tyrosine kinase activity and several autophosphorylation sites

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3
Q

How are monomeric RTKs activated?

A

Ligand binding induces dimerization of two monomers

Each monomer phosphorylates a tyrosine residue in the other’s activation loop

Conformational change in activation loops unblocks the tyrosine kinase activity

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4
Q

What two things can fully active catalytic domains of RTKs phosphorylate?

A

Cytosolic segments of the receptor dimer – act as docking sites

Intracellular signaling molecules

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5
Q

Describe the structure of the insulin and IGF-1 receptors.

A

Two external alpha subunits, each with a ligand binding site

Two transmembrane beta subunits, the cytoplasmic portion of each contains a tyrosine kinase domain.

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6
Q

What happens after cross phosphorylation of the B subunits in the insulin receptor?

A

Insulin receptor subustrates (IRS) associates with the activated receptor by means of a phosphotyrosine binding domain (PTB)

IRS is then phosphorylated on specific tyrosine residues by the receptor.

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7
Q

What is the role of IRS in the insulin response?

A

Serve as a docking site for other intracellular signaling proteins via their SH2 domains

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8
Q

What are phosphotyrosine phosphatases?

A

important negative regulators of insulin and IFG signaling

Acts by dephosphorylating tyrosine residues on activated insulin and IGF-1 receptors and on IRS proteins

Also act on other RTKs in this manner as a form of inhibition

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9
Q

What purposes do binding of intracellular signaling proteins to the receptor serve?

A

Localizes them to the plasma membrane

Enables them to interact with other proteins that are associated with the receptor

Activates the signal transuction pathways to which the intracellular signaling proteins are coupled

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10
Q

What are Src homology 2 (SH2) domains?

A

Highly conserved region that enables an intracellular signaling protein to recognize and bind specific phosphotyrosine residues

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11
Q

What is Phospholipase C-gamma?

A

A signaling protein that is activated when it binds to an active RTK.

Catalyzes the breakdown of PIP2 to DAG and IP3

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12
Q

How is the Ras/MAPK pathway activated?

A

A GEF docks with an RTK and activates Ras

Ras phosphorylates the first kinase in the pathway (Raf)

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13
Q

What pathway can virtually all RTKs activate?

A

The Ras/MAP pathway

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14
Q

What happens when MAPK is phosphorylated?

A

Dimerizes

Phosphorylates p90RSK

Phosphoryaltes TCF, a transcription factor

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15
Q

What is the function of p90RSK?

A

Phosphorylated by MAPK

Phosphorylates SRF (serum response factor)

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16
Q

What is the function of SRF and TCF?

A

Once they are activated, the associate in the promotor region of the regulated gene and stimulate transcription

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17
Q

What are Cytokines?

A

Family of protein/peptide signaling molecules that play a major role in regulating the proliferation and differentiation of blood cells and cells of the immune system

Activate the JAK/STAT pathway

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18
Q

What are JAK proteins?

A

Tyrosine kinases that are bound to cytokine receptors

19
Q

How are JAK proteins activated?

A

Ligand binding of a cytokine receptor promotes dimerization (or the dimer is preformed), this allows each JAK protein to cross phosphorylate the other’s activation loop.

Active JAKs phosphorylate receptor tyrosine residues that serve as docking sites

20
Q

What are STAT (Signal Transduction and Activation of Transcription) proteins?

A

Transcription factors that are the major target of JAKs.

Once phosphorylated, STAT proteins form dimers and translocate to the nucleus where they activate gene transcription

21
Q

What are four mechanisms of inhibiting tyrosine kinases

A

Phosphotyrosine phosphatases

PKC - phosphorylates specific serine and threonine residues on the receptor

Desensitization

Certain SH2 signaling proteins with a ubiquitin ligase domain that targets the receptor for degredation

22
Q

What is SHP1?

A

Phosphotyrosine phosphatase with two SH2 domians, normally one blocks the phosphatase domain

When a receptor is stimulated, the covering SH2 docks on the receptor.

The exposed phosphatase removes a phosphate in the activation lip of JAK, reducing its activity

23
Q

What is PI 3-kinase and what is the function of its product?

A

Catalyzes the addition of a 3-phosphate to phosphoinositide substrates in the PM to form PI 3-phosphates

PI 3-phosphates function as docking sites for certain signal transduction proteins

24
Q

What is a Plextrin homology (PH) domain?

A

Domain on certain proteins that binds 3-phosphates with high affinity

25
Q

How is Akt(PKB) activated?

A

Stimulation by ligand catalyzes the formation of PI 3-phosphate.

The PHB domain of PKB binds to PI 3-Phosphate, inducing partial activation.

PDK1 and PDK2 also phosphorylate PKB, causing its full activation

26
Q

What is the role of the PKB/Akt pathway?

A

Plays important role in promoting cell division and survival and in the regulation of metabolism

27
Q

What does NF-kB regulate?

A

The transcription of numerous genes involved in the inflammatory and immune responses

28
Q

What is NF-kB?

A

a heterodimer that is sequestered in the cytoplasm by an inhibitory protein called IkBa

Once activated, enters the nucleus and promotes the transcription of target genes

29
Q

What is the function of I-kB kinase?

A

Activated by a signaling cascade in response to an immune signaling molecule

Phosphorylates two serine residues on the N-terminal portion of I-kBa

30
Q

What occurs when I-kBa is phosphorylated?

A

E3 ubiquitin ligase binds to it and triggers degredation by a proteosome

31
Q

What protein products does NF-kB transcribe?

A

Phospholipase A2 and cyclooxygenase

NO synthase

Cytokines (TNFa and interleukin-1)

I-kB

32
Q

What is the negative feedback loop that inhibits NF-kB activity?

A

NF-kB transcribes the I-kB gene which is responsible for its inhibition

33
Q

What is NO synthase?

A

Creates NO through the deamination of arginine

34
Q

What is the role of NO?

A

Released from endothelial cells in response to acetylcholine

Diffuses into underlying vascular smooth muscle cells

Activates guanylyl cyclase

35
Q

What is cGMP-dependent protein kinase?

A

Phosphorylates serine or threonine on target proteins when activated by 2 cGMP molecules

Promotes vasorelaxtion via its pathway

36
Q

Receptors for thyroid hormones, steroid hormones, Vit D and retinoids are what kind of receptors and how do they act?

A

Intracellular receptors that act as transcription factors when bound

37
Q

What domains are present in intracellular receptors?

A
  • N-terminal with a ligant-independent transactivation domain
  • DNA binding domain - zinc finger
  • Hinge region - gives structural flexibility
  • Ligand-binding domain
38
Q

What is bound to a steroid hormone receptor in an inactive state?

A

Heat shock proteins

39
Q

What is the mechanism of action of steroid hormones?

A

When they bind to the receptor, the receptor translocates to the nucleus and binds specific DNA sequences called steroie-response elements (SRE)

They can either recruit HATs or HDACs and activate or repress transcription

40
Q

What are examples of drugs that block the action of steroid hormones?

A

Flutamide - androgen receptor antagonist

RU486 - progesterone receptor antagonist

41
Q

What is the state of an unoccupied Thyroid hormone receptors?

A
  • do not form complexes with Hsp’s

- bind tightly to DNA even in the absence of hormone and repress gene transcription by recruiting proteins and HDAC

42
Q

What are TREs?

A

Thyroid response elements

Location of thyroid receptor binding on the DNA

43
Q

What is the preferred arrangement of a THR?

A

Heterodimer with the RXR receptor (retinoid X receptor)

44
Q

What does thyroid hormone binding cause?

A

Promotes the dissociation of corepressor proteins and the association of coactivator proteins

However, in certain genes it can also cause repression, where the gene is active in the absence of TH

EOM Test 3 (19 decks)

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