Cell Signaling Objectives - Sanchez

7/25/2019 Cell Signaling Objectives - Sanchez

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Principles of Signal Transduction: Objectives

1. Be able to compare and contrast the overall properties ofendocrine and synaptic signaling mechanisms.

a. Endocrine Signaling echanism:i. !ormone is secreted by an endocrine gland and is

carried" via the bloodstream" to a distant target cell

ii. Signaling is S#O$1. %elies on passive di&usion and blood 'o(

iii. Signals are )*#+TE1. %eceptors have high speci,city and a-nity for

the signala. hemically based speci,city and a-nity

/. There is a slo( termination of the response0slo( dissociation rate

iv. Endocrine cells secrete many ligands 2 thus thetarget cells must be speci,c (ith a high a-nity

v. E3ample: Steroids

b. Synaptic Signaling echanism:i. Signaling is 45ST

1. +ses electrical impulses over short distanceii. Signals reach high local concentrations

1. %eceptors have lo( a-nity for the signala. echanically based 0based on the

placement of the synapses/. There is a rapid termination of the response

06uic7 dissociation rateiii. Secrete fe( distinct ligands 2 the speci,city comes

from the precise nerve8target cell contact point

iv. E3amples: Peptides and proteins9 catecholamines


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/. Be able to identify the four major types of signal transductionpath(ays and give e3amples of ligands and cellular responsesfor each.

a. %eceptor Tyrosine inasei. #igands: *nsulin" lots of gro(th factors

ii. *nsulin %eceptor Signaling:1. %eceptor binds t(o signal compounds 0in this

case" insulin peptide (hich activates atyrosine auto7inase. This also phosphorylates*%S;1 0ro(th: *%S1 phosphorylates Shp" activating

%as.a. %as activates 5P (hich activates

Transcription factors (hich promotegro(th

/. >lucose +pta7ea. *%S;1 phosphorylates P1?" initiating a

phosphorylation cascadei. #eads to >#+T@ 0transporters of

glucose onto the plasmamembrane

?. >lycogen )eposistiona. *%S1 phosphorylates P1?" initiating a

phosporylation cascadei. #eads to stimulation of enAymatic

steps in the conversion of glucose

to glycogenb. > Protein;#in7ed %eceptors

i. #igands: a great variety use > Protein;#in7ed%eceptors

1. atecholamines" Ts" Peptide hormonesCii. / possible cellular responses:

1. c5P Signal Path(aya. c5P activates c5P;dependent Protein

inase 0P5 by phosphorylating P5i. inase is a tetramer

1. / c5P;binding chains

/. / catalytic chainsb. Binding causes release of activated

catalytic subunitsc. atalytic units phosphorylate substrates

0usually enAymesd. oderation or reversal of response is

achieved via:i. )ephosphorylation of substrates


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1. By phosphatasesii. )egradation of c5P

1. By phosphodiesterases 0P)E


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/. Phosphatidylinositol Path(aya. !ormone signal causes increase in

cytosolic aDD and activation of P"leading to / distinct 0but interactingchain of events:

i. aDD binds to almodulin 0a1. yosin #ight hain inase

0# phosphorylatesmyosin

a. auses interaction (ithactin and musclecontracts

/. itric O3ide Synthase 0OSii. Protein inase phosphorylates a

variety of enAymes and proteins1. *on channels 0li7e aD8!D

pumpa. Phosphorylation leads

to increase of cellularp! and proliferation

/. 5ctivation of transcriptionfactors controlling genee3pression

c. *ntracellular %eceptors 0steroidsi. E3amples of ligands: >lucocorticoid" mineralcorticoid"

progesterone" estrogen" androgen" vitamin )" thyroidii. Three domains

1. Transcription activation )omaina. %esponsible for interaction promoting

activity by %5 polymerasei. Thus" ommunication (ith Pol

/. )5 Binding )omaina. Site of direct interaction (ith )5 in the

promoter region of genesi. Thus" %ecognition of !ormone

%esponse Elements?. #igand Binding )omain.

a. Site of high;selectivity binding by steroid

hormonesi. Thus" Binding Site

iii. / 5ctivated Steroid %eceptors recruit the !istone5cetyl Transferase 0!5T omple3

1. #eading to acetylation of histonesa. auses )5 to un(ind

i. 5llo(ing the binding of thetranscription apparatus.


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d. #igand >ated hannelsi. onverts e3tracellular signals into electrical impulsesii. Occurs bet(een nerves and target cells 0ated channel opens" allo(ing entry of ionsiii. E3ample: icotinic 5cetylchnoline %eceptor:

1. hannel opening re6uires / molecules of ligand/. hannel opens only brie'y

a. loses (hile still ligated?. #igand dissociates" returning channel to resting

state

@. )issociated 5h is hydrolyAed bycholineresterase

?. Be able to identify or describe the 7ey steps and moleculesinvolved in each of the four major path(ays" including structureand location of receptors" /ndmessenger molecules 0includingcalcium and nitric o3ide" e&ector enAymes" and substrates.

a. #igand;>ated hannelsi. ey Steps:

1. erve terminal releases neurotransmittersa. ia fusion of storage vesicles (ith plasma

membrane

/. T binds channels present in synapse region?. >ated channel opens" allo(ing entry of ions

ii. olecules involved:1. eurotransmitters

a. 5h" >5B5" Serotonin" >lutamate">lycineC

iii. Structure of receptors:1. omposed of F transmembrane polypeptides

a. Each chain GFHH 55s and traversesmembrane four 0@ times

/. 1 heli3 of each chain contains polar 55s:


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v. /ndmessenger molecules:vi. E&ector EnAymes:

1. holineresterase 0hydrolyAes dissociated 5hvii. Substrates:


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b. %eceptor Tyrosine inases:i. ey Steps:

1. #igand binding to the insulin receptor 0*%a. *nduces phosphorylation on tyrosine

residues on the intracellular domain

b. / ligands of insulin peptide are re6uiredfor full activation

ii. olecules involved:1. *nsulin Peptide/. *%S1?. %as 0for 5P 7inase cascade to promote gro(th

factors@. P1? 0is phosphorylated by *%S1" initiates

phosphorylation cascadeiii. Structure of receptors:

1. Single transmembrane alpha heli3

/. E3ample: *nsulina. / beta and / alpha chains 0sul,de bond

connects themb. 5lpha chains: contain hormone;binding

sitec. Beta chains: traverse the membrane and

contain tyrosine 7inase domainiv. #ocation of receptors:

1. On the plasma membrane 0transmembrane/. E3tracellular domain

a. #igand;binding site

?. *ntracellular domaina. Tyrosine 7inase activity

v. /ndmessenger molecules:1. *%S1/. %as0for 5P 7inase cascade to promote gro(th

factors?. P1? 0is phosphorylated by *%S1" initiates

phosphorylation cascadevi. E&ector EnAymes:

1. 5P inase 0activates transcription factors topromote gro(th

vii. Substrates:


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c. Steroid 0*ntercellular %eceptors:i. ey Steps:

1. / #igand;ed Steroid %eceptors recruits a co;activator that contains the enAyme"

/. That enAyme leads to acetylation of histones?. The acetylated histones allo( the )5 to

un(ind@. The un(ound )5 allo(s for the binding of

general transcription factors 0such as Pol **ii. olecules involved:

1. S% 0Steroid %eceptor/. !SP?. *P@. o5 omple3F. T5T5 0gene e3pression begins here via %5

transcriptioniii. Structure of receptors:

1. !/ 2 Transcription activation domain 2 )5binding domain 2 #igand binding domain 2OO!

/. %eceptors are al(ays


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d. >;Protein #in7ed %eceptorsi. Structure of receptors:

1. enerates @ intracellular and

e3tracellular loops

b. E3tracellular amino terminus:i. #igand binding site

c. *ntracellular loops:i. > Protein *nteractionii. Phosphorylation;mediated

inactivation1. $hen ?rdloop is

phosphorylated" the receptoris inactivated

ii. c5P Signaling:1. ey Steps:

a. !ormone stimulateion causes rapidincrease in c5P

b. 5denylate cyclase cleaves 5TP togenerate c5P and pyrophosphate

i. *%%EE%S*B#E stepc. )egradation of c5P by

phosphodiesterasei. Jields FK;5P


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/. olecules involved:a. c5P" P5 0c5P;dependent protein

7inase?. #ocation of receptors:

a. On Plasma membrane

i. 5lpha chain:1. Binds and hydrolyAes >TP/. 5ctivates adenylate cyclase

ii. Beta and >amma chains:1. 5nchors alpha chain to the

cytoplasmic face@. /ndmessenger molecules:

a. yclic 5P 0c5PF. E&ector EnAymes:

a. 5denylate cyclase cleaves 5TP togenerate c5P and pyrophosphate

i. *%%EE%S*B#E stepb. )egradation of c5P by

phosphodiesterasei. Jields FK;5P

L. Substrates:iii. aDD8Phosphoinositide Signal Path(ay:

1. ey Steps:

/. olecules involved:a. am 0almodulin

?. #ocation of receptors:a. Plasma membrane

i. On they cytosolic face@. /ndmessenger molecules:

a. )iacylglycerol 0)5>


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b. *nositol Trisphosphate 0*P?c. aDD *on

F. E&ector EnAymes:a. # 0phosphorylates myosin" causing

muscle contraction

b. itric O3ide Synthase 0OSc. Protein inase 0phosphorylates lots of

enAymes and proteinsL. Substrates:

@. Be able to describe the major mechanisms by (hich each signalpath(ays can be inhibited.

a. Tyrosine inase" Steroid" and #igand;>ated hannels:i. )o(n;regulation of ell Surface %eceptorsii. Prolonged hormone e3posure leads to receptor

degradation

iii.b. >;#in7ed

i. *nactivation of receptors via phosphorylation:1. Excess hormone

a. %esults in receptor that can bind

hormone but not activate > protein/. Phosphorylation of serines and threoninesonintracellular loops

?. A-kinase,rst to phosphorylate (hen c5Plevels get too high" follo(ed by BARK

@. 4ully phosphorylated receptor is furtherbloc7ed from > protein by beta arrestin

Cell Signaling Objectives - Sanchez

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