PHA 4107 Lecture Notes - Lecture 4: Vascular Endothelial Growth Factor, Receptor Tyrosine Kinase, Sh3 Domain

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12 Jul 2018

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These receptors undergo autophosphorylation (catalyze their own phosphorylation) and can transphorylate other proteins in response to a ligand. Classes of receptor tyrosine kinases (rtks: epidermal growth factor (egf-r) receptor family includes, egfr1 (erbb1, egfr2 (erbb2, her2/neu, egfr3,4 (erbb3,4 or her3,4, insulin receptor, platelet-derived growth factor (pdgf, fibroblast growth factor (fgf, vascular endothelial growth factor (vegf) The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up regulates the enzymatic activity of the intracellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules. Grb2 is an adaptor protein containing both sh2 and sh3 domains. How do you achieve specificity of protein-protein interactions: different sh2 domains have different affinities for a given phosphotyrosine (surrounding sequences can confer specificity) The sequences c-terminal to the consensus phosphotyrosine binding domain determine if a protein will bind to an rtk and (if it is a substrate) be phosphorylated.

Related Questions

The binding of platelet derived growth factor (PDGF) to the PDGF receptor stimulates phosphorylation of 8 tyrosines in the receptor's cytoplasmic domain. The enzyme phosphatidylinositol 3'kinase (PI 3-kinase) binds to one or more of the phophotyrosines through its SH2 domains and is thereby activated. To identify the activation phosphotyrosines, you synthesize 8 pentapetides that contain the critical tyrosines (at the N-terninus) in their phosphorylated or unphosphorylated forms. You then mix an excess of each of the various pentapeptides with phosphorylated PDGF receptor and PI 3-kinase. Immunoprecipitation of the PDGF receptor will bring down any bound PI 3-kinase, which can be assayed by its ability to add 32P-phosphate to its substrate.

A) Draw a flow diagram showing how this assay works.

B) Do your results support the notion that PI-kinase binds to phosphotyrosines in the activated PDGF receptor? Why or why not?

C) THe amino acid sequences of the PDGF receptor pentapeptide tested above (number accodingly to the position of tyrosine in the PDGF receptor) and peptide segments that are known to bind to PI 3-kinase in other activated receptors are shown below. Which amino acid residues are most important and why?

684 YSNAL YMMMR (FGF receptor)

708 YMDMS YTHMN (insulin receptor)

719 YVPML YEVML (hepatocyte growth factor receptor)

731 YADIE YMDMK (steel factor receptor)

739 YMAPY YVEMR (CSF-1 receptor)

743 YDNYE

746 YEPSA

755 YRATL

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QUESTION 1

Which of the following is an example of an extracellular signal molecule?

	a.	IP₃
	b.	cAMP
	c.	Insulin
	d.	Diacylglycerol

2 points

QUESTION 2

Nuclear hormone receptors _____

	a.	Bind to water soluble ligands
	b.	Activate second messengers
	c.	Regulate transcription in response to ligand binding
	d.	Are normally located on the plasma membrane

2 points

QUESTION 3

Which of the following does not occur when a receptor tyrosine kinase is bound by ligand?

	a.	Phosphorylation of the RTK
	b.	Cytoplasmic proteins bind the phosphorylated RTK
	c.	Dimerization of the RTK
	d.	The RTK binds to DNA to regulate transcription

2 points

QUESTION 4

Which of these is a logical signal-transduction pathway?

	a.	An intracellular receptor activates phospholipase C, which cleaves a membrane protein to form IP₃, which then activates the opening of an ER channel protein, which releases cyclic AMP into the cytoplasm, where it binds to an intracellular enzyme that carries out a response.
	b.	A G-protein-linked receptor activates G protein, which activates phospholipase C, which cleaves a membrane lipid to form IP₃, which binds to a calcium channel on the ER, which opens to release calcium ions into the cytoplasm, which bind to an intracellular enzyme that carries out a response.
	c.	An ion-channel receptor opens, allowing a steroid hormone to enter the cell; the steroid hormone then activates protein kinases that convert GTP to GDP, which binds to an intracellular enzyme that carries out a response.
	d.	A tyrosine-kinase receptor activates adenylyl cyclase, which activates phospholipase C, which converts ATP into cyclic AMP, which binds to an intracellular enzyme that carries out a response.

2 points

QUESTION 5

Which of the following is an example of signal amplification?

	a.	activation of an enzyme molecule
	b.	activation of a specific gene by a growth factor
	c.	Breakdown of many cAMP molecules
	d.	activation of 100 molecules by a single signal binding event

2 points

QUESTION 6

Consider a signal transduction pathway that utilizes cAMP as a second messenger to activate PKA (Protein Kinase A). Which of the following situations will result in the cellular response?

		The G protein releases GDP and binds to GTP
		The target protein (adenylyl cyclase) is inactive
		The regulatory subunits of PKA (Protein Kinase A) are bound to the catalytic subunits
		The appropriate G protein is bound to GDP

2 points

QUESTION 7

Which of the following is found in only some signal transduction pathways? [In other words, which is not found in all signal transduction pathways?]

		Receptor protein
		Extracellular signal molecule
		Intracellular signaling molecule
		Cellular response
		Effector protein

2 points

QUESTION 8

The enzyme that specifically catalyzes the conversion of ATP to cAMP is:

		Adenylyl phosphatase
		Adenylyl kinase
		Adenylyl dehydrogenase
		Adenylyl cyclase

2 points

QUESTION 9

If an animal cell suddenly lost the ability to produce GTP, what might happen to its signaling system?

		It would use ATP instead of GTP to activate and inactivate the G protein on the cytoplasmic side of the plasma membrane.
		It would not be able to activate and inactivate the G protein on the cytoplasmic side of the plasma membrane.
		It would employ a transduction pathway directly from an external messenger.
		It would be able to carry out reception and transduction but would not be able to respond to a signal.

2 points

QUESTION 10

A hormone signal is sent from the brain to other parts of the body via the bloodstream. Why do only certain cells respond to this signal?

		Hormones do not last long enough in the bloodstream to stimulate a cellular response
		Only cells that have a specific transcription factor gene will be able to respond to the signal
		Only cells in the immediate vicinity of the cell sending the signal will respond
		Only cells that have a receptor for the specific signal will be able to respond to it

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PHA 4107 Lecture Notes - Lecture 4: Vascular Endothelial Growth Factor, Receptor Tyrosine Kinase, Sh3 Domain

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