cell signaling and signal transduction (2)

7/31/2019 Cell Signaling and Signal Transduction (2)

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Overview of Signaling Transduction Pathway
http://upload.wikimedia.org/wikipedia/commons/f/fb/Signal_transduction_pathways.png


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Many biological processes require various cells to work together and to coordinate their activities. To make this possible,cells have to communicate with each other, which is

accomplished by a process called cell signaling .

Cell signaling* makes it possible for cells to talk to each other and for an organism to function as a coherent system*affects virtually every aspect of cell structure and function*intimately involved in the regulation of cell growth anddivision (important in understanding how a cell lose its

ability to control cell division and develop into a malignanttumor)


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Why do cells communicate?- cells communicate in order to proliferate, differentiate,migrate and maintain functional state.

- cell-cell signalling permits coordinated function ofcells within and between tissues, up to the organismlevel

- signalling informs cells what they are, where theyare, and what they should be doing.


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The Basic Elements of Cell Signaling SystemsSignaling cell

Extracellular signaling molecule (1 st messenger)

P

Transmembranereceptor

Effector

2nd messenger

Activated targetprotein

TranscriptionSurvival

Protein synthesisCell deathMetabolic change

1

22

33 4a

8 8

7

6

7

6

5

4

99


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Cell-Cell Signaling by extracellular signals occurs

in the following manner: a. synthesisb. release of the signaling molecule by the signaling cellc. transport of the signal to the target cell

d. binding of the signal by a specific receptor proteinleading to its activation

e. initiation of one or more intracellular signal- transductionpathways by the activated receptor

f. specific changes in cellular function, metabolism, or

developmentg. removal of the signal which often terminates the cellular response


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Cells usually communicate with each other through extracellular messenger molecules

Chemical messengers-A variety of compounds that serve as signals between cells

eg. Hormones produced at great distances from their targettissues and are carried by blood to various sites in thebody

Growth factors- released locally acting only on nearby tissues

Ligand chemicalmessenger thatbinds to a receptor

Receptors- specificallyrecognizes and binda particular ligand

-found em-bedded within the Pof the cell receivingthe signal or foundinside the cell


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Classifications of Signal Transducing ReceptorsSignal transducing receptors are of three general classes:

1. Receptors that are coupled, inside the cell, to GTP-binding and hydrolyzing proteins(termed G-proteins). Receptors of the class that interact with G-proteins all have astructure that is characterized by 7 transmembrane spanning domains. These

receptors are termed serpentine receptors. Examples of this class are the adrenergicreceptors, odorant receptors, and certain hormone receptors (e.g. glucagon,angiotensin, vasopressin and bradykinin).2. Receptors that penetrate the plasma membrane and have intrinsic enzymaticactivity. Receptors that have intrinsic enzymatic activities include those that aretyrosine kinases (e.g. PDGF, insulin, EGF and FGF receptors), tyrosine phosphatases(e.g. CD45 [cluster determinant-45] protein of T cells and macrophages),guanylate cyclases (e.g. natriuretic peptide receptors) and serine/threonine kinases(e.g. activin and TGF- receptors). Receptors with intrinsic tyrosine kinase activity arecapable of autophosphorylation as well as phosphorylation of other substrates.Additionally, several families of receptors lack intrinsic enzyme activity, yet arecoupled to intracellular tyrosine kinases by direct protein-protein interactions.

2nd messengers - small molecules or ions that relay the signals from onelocation in the cell such as plasma membrane , to the interior of thecell, initiating a cascade of changes within the receiving cell.


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3. Receptors that are found intracellularly and upon ligand binding migrate to thenucleus where the ligand-receptor complex directly affects gene transcription. Becausethis class of receptors is intracellular and functions in the nucleus as transcriptionfactors they are commonly referred to as the nuclear receptors . Receptors of this classinclude the large family of steroid and thyroid hormone receptors. Receptors in thisclass have a ligand-binding domain, a DNA-binding domain and a transcriptionalactivator domain


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G-Protein Coupled ReceptorsThere are several different classifications of receptors that couple signal transduction toG-proteins. These classes of receptor are termed G-protein coupled receptors, GPCRs.Well over 1000 different GPCRs have been cloned, most being orphan receptors having

no as yet identified ligand. Three different classes of GPCR are reviewed:1. GPCRs that modulate adenylate cyclase activity. One class of adenylate cyclasemodulating receptors activate the enzyme leading to the production of cAMP as thesecond messenger. Receptors of this class include the -adrenergic, glucagon andodorant molecule receptors. Increases in the production of cAMP leads to an increase inthe activity of PKA in the case of -adrenergic and glucagon receptors. In the case of

odorant molecule receptors the increase in cAMP leads to the activation of ion channels.In contrast to increased adenylate cyclase activity, the 1-type adrenergic receptors arecoupled to inhibitory G-proteins that repress adenylate cyclase activity upon receptoractivation.2. GPCRs that activate PLC leading to hydrolysis of polyphosphoinositides (e.g. PIP 2)generating the second messengers, diacylglycerol (DAG) and inositoltrisphosphate (IP 3).This class of receptors includes the 2-adrenergic , angiotensin, bradykinin andvasopressin receptors.3. A novel class of GPCRs are the photoreceptors. This class is coupled to a G-proteintermed transducin that activates a phosphodiesterase which leads to a decrease in thelevel of cGMP. The drop in cGMP then results in the closing of a Na +/Ca 2+ channel leadingto hyperpolarization of the cell.


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Cyclic AMP is a SecondMessenger Used by OneClass of G Proteins


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cAMP Synthesis

Major pathways by which G-protein-linkedcell-surface receptors generate smallintracellular mediators.


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Many G Proteins Use InositolTriphosphate and Diacylglycerol

As Second Messengers


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Regulated Function Target Tissue MessengerPlatelet activation Blood platelets Thrombin

Muscle contraction Smooth muscle Acethlcholine

Insulin secretion Pancreas, endocrine Acetylcholine

Amylase secretion Pancreas, endocrine Acetylcholine

Glycogen degradation Liver Antidiuretic hormone

Antibody production B lymphocytes Foreign antigens

Table5. Examples of Cell Functions Regulated by Inositol Triphosphate and Diacylglycerol


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Calcium Release Following Fertilization of Animal Eggs

Fig. 5 Transient Increase in free Ca 2+ concentration that occurs in an egg cell imme-

diately after fertilization


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Calcium release is necessary for two crucial events:1. Slow block to polyspermy caused by alterations of the vitelline

envelope rendering the egg unable to bind additional sperm,thereby preventing more than one sperm from fertilizing theegg.

2. Egg activation- involves the resumption of many metabolicprocesses, reorganization of the internal contents of the egg,and other events that initiate the process of embryonicdevelopment.


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Nitric oxide couples G Protein-Linked Receptor StimulationIn Endothelial Cells to Relaxation of Smooth Muscle CellsIn Blood Vessels

Fig 5. The Action of Nitric Oxide onBlood Vessels. The binding of acetyl-choline to endothelial cells triggers

the production of nitric oxide, whichdiffuses into the adjacent smoothmuscle cells and stimulates guanylylcyclase, thereby leading to musclerelaxation


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Protein Kinase-Associated Receptors

Fig. 1 . Reversible protein phosphorylation. A protein kinase moves a phosphate group(P) from ATP (ADP(P)) to the protein. The biological properties of the protein is therebyaltered. There is also a protein phosphatase that is able to remove the phosphate group.The amount of phosphate that is associated with the protein is thus determined by therelative activities of the kinase and the phosphatase


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Fig. 2 . Protein phosphorylation reactions that are coupled in series can act as abiological amplifier. We are dealing with a controlled chain reaction. When the level of glucose in blood is lowered the amount of the hormone adrenaline rises. This elevatesthe cyclic AMP content in the liver cell. This activates a cyclic AMP dependent proteinkinase, which phosphorylates a kinase that in turn switches on the glycogen degradingenzyme phosphorylase. Hence glycogen is converted to glucose which can enter theblood stream. When the blood glucose rises the adrenaline level in blood goes down.The stimulation is turned off and the phosphatase reactions take over turning theglucose production down. In muscle cells a rise in calcium is the signal for muscular

work. Calcium ions also switch on the phosphorylation reactions so that the muscle isprovided with the required energy


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Protein Kinase-Associated Receptors-not only function as receptors but are also protein kinases-when they bind to the appropriate ligand, their kinase activity isstimulated and they transmit signals through a cascade of phospho-rylation events within the cell

Receptor Tyrosine Kinases Aggregate and Undergo Autophosphorylation

-many receptor tyrosine kinases trigger a chain of signal transductionevents inside the the cell that ultimately lead to:

a) cell growthb) proliferation

c) specialization of cells known as differentiation

SH2 domain - Src-homology 2-signaling proteins interact with one another in a sequential

manner because they contain portion of the protein that

recognizes one of these phosphorylated tyrosines


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-receptor tyrosine kinases can activate several different signal transduction pathwaysat the same time. These include the inositol-phospholipid-calcium second messengerpathway and the Ras pathway which ultimately activates the expression of genesInvolved in growth or development.

Receptor Tyrosine Kinases Initiate a Signal Transduction CascadeInvolving Ras and MAP Kinase

Ras small monomeric G protein- important in regulating the growth of cells- needs the help of another protein called guanine-nucleotide release protein

(GNRP)-Sos = a GNRP that activates Ras

= so called bec it was originally identified from a genetic mutation in

fruit flies called the Son of Sevenless that results in the failure of cells in the compound eye to develop properly

Mitogen-activated protein kinases or MAP kinases (MAPKs)-activated when cells receive a stimulus to grow and divide(such a signalis sometimes called a mitogen, hence the name of the kinase)

AP-1 - a transcription factor (appears to stimulate production of proteins neededfor cells to grow and divide)


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*Receptor tyrosine kinases activate a variety of other signaling pathways (see Fig. 10-17)

Growth Factor as MessengersGrowth Factors

- present within serum and members of various classes of proteins

Growth Factor Target Cells Type of Receptor Complex

Epidermal Growth Factor

(EFG)

Wide variety of epithelial

and mesenchymal cells

Tyrosine kinase

Transforming growth factor- (TGF- )

Same as EGF Tyrosine kinase

Platelet-derived growthfactor (PDGF)

Mesenchyme, smoothmuscle, trophoblast

Tyrosine kinase

Transforming growth factor-(TGF- ) Fibroblastic cells Serine-threonine kinase

Fibroblast growth factor Mesenchyme, fibroblasts,many other cell types

Tyrosine kinase

Interleukin-2 (IL-2) Cytotoxic T-lymphocytes Complex of three subunits

Table 10. Examples of Growth Factor Families


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*Disrupting of Growth Factor signaling through receptor tyrosinekinases can have dramatic effects on embryonic development

-fibroblast growth factors (FGFs) and fibroblast growth factorreceptors (FGFRs)

used in signaling events in both adult animals and embryos FGFRs play an important role in the development of cells derived from

the middle embryonic cell layer of early embryos known as mesodermMesoderm forms many cell types, including muscle, cartilage, bone

and blood cells as well as the forerunner of the vertebral column.(When specific FGFRs fail to function properly, the development of particular mesodermal tissues is affected)-cause dominant negativemutations = can have dramatic effects on cells in developing embryos

Eg. In humans, dominant mutations in the transmembrane portion of the

FGFR-3 gene result in the most common form of dwarfism known asachondroplasia. (Heterozygous individuals have abnormal bone growthin which the long bones suffer from abnormally slow ossification)


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Cell Signals and Programmed Cell Death-cell signaling also regulates APOPTOSIS

-different from another cell death known as necrosis(which sometimesfollows massive tissue injury)

Differences:NECROSIS involves the swelling and rupture of the injured cellsAPOPTOSIS involves specific events that leads to the dismantling of the internal

contents of the cell and affected cell is engulfed by other nearby cellsthat act as scavengers to remove the resulting cellular debris.

- key event in many biological processes (eg. Removal of the webbingbetween digits(fingers and toes) during the development of hands andfeet the resorption of the tail of tadpoles when they undergo metamor-phosis , and the pruning of neurons that occurs in human infants during

the first few months of life as connections mature within the developingbrain. )- in adult humans, millions of cells such as blood cells die every minute.


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Caspases - enzymes once activated cleave other proteins within cells, resulting in efficientand precise killing of the cell in which they are activated.-the caspases required for the death of a particular cell vary but the basic sequenceof events is similar in all cases


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Regulated Functions Target Tissue HormoneGlycogen degradation Muscle, liver Epinephrine

Fatty acid production adipose Epinephrine

Heart rate, blood pressure cardiovascular Epinephrine

Water reabsorption kidney Antidiuretic hormone

Bone resorption bone Parathyroid hormone

Table 10. 2 Examples of Cells Functions Regulated by cAMP


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Convergence, divergence and crosstalk among Signaling pathways

Signals from a variety of unrelated receptors each binding to itsown ligand, can converge to activate a common effector such asRas or Raf

Signals from the same ligand, such as EGF or insulin, can divergeto activate a variety of different effectors, leading to diverse

cellular responses

Signals can be passed back and forth between different

pathways, a phenomenon known as crosstalk

cell signaling and signal transduction (2)

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