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Cell Signaling and Signal Transduction: Communication Between Cells II.

Messengers and Receptors

Overview of Signaling Transduction Pathway

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 and division (important in understanding how a cell lose its ability to control cell division and develop into a malignant tumor)

Why do cells communicate?

- cells communicate in order to proliferate, differentiate, migrate and maintain functional state. - cell-cell signalling permits coordinated function of cells within and between tissues, up to the organism level - signalling informs cells what they are, where they are, and what they should be doing.

The Basic Elements of Cell Signaling Systems

Signaling cell

Extracellular signaling molecule (1st messenger)

Transmembrane receptor 2 3 4 5 2 3 4a




Activated target protein

8 9
Transcription Survival Protein synthesis Cell death Metabolic change

8 9

Cell-Cell Signaling by extracellular signals occurs in the following manner:

a. b. c. d.
e. f.


synthesis release of the signaling molecule by the signaling cell transport of the signal to the target cell binding of the signal by a specific receptor protein leading to its activation initiation of one or more intracellular signal- transduction pathways by the activated receptor specific changes in cellular function, metabolism, or development removal of the signal which often terminates the cellular response

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 target tissues and are carried by blood to various sites in the body Growth factors- released locally acting only on nearby tissues

Ligand chemical messenger that binds to a receptor

Receptors-specifically recognizes and bind a particular ligand -found embedded within the PM of the cell receiving the signal or found inside the cell

2nd messengers- small molecules or ions that relay the signals from one location in the cell such as plasma membrane , to the interior of the cell, initiating a cascade of changes within the receiving cell. Classifications of Signal Transducing Receptors Signal 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 a structure that is characterized by 7 transmembrane spanning domains. These receptors are termed serpentine receptors. Examples of this class are the adrenergic receptors, odorant receptors, and certain hormone receptors (e.g. glucagon, angiotensin, vasopressin and bradykinin). 2. Receptors that penetrate the plasma membrane and have intrinsic enzymatic activity. Receptors that have intrinsic enzymatic activities include those that are tyrosine 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 are capable of autophosphorylation as well as phosphorylation of other substrates. Additionally, several families of receptors lack intrinsic enzyme activity, yet are coupled to intracellular tyrosine kinases by direct protein-protein interactions.

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

G-Protein Coupled Receptors

There are several different classifications of receptors that couple signal transduction to G-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 cyclase modulating receptors activate the enzyme leading to the production of cAMP as the second messenger. Receptors of this class include the -adrenergic, glucagon and odorant molecule receptors. Increases in the production of cAMP leads to an increase in the 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 are coupled to inhibitory G-proteins that repress adenylate cyclase activity upon receptor activation. 2. GPCRs that activate PLC leading to hydrolysis of polyphosphoinositides (e.g. PIP2) generating the second messengers, diacylglycerol (DAG) and inositoltrisphosphate (IP3). This class of receptors includes the 2-adrenergic , angiotensin, bradykinin and vasopressin receptors. 3. A novel class of GPCRs are the photoreceptors. This class is coupled to a G-protein termed transducin that activates a phosphodiesterase which leads to a decrease in the level of cGMP. The drop in cGMP then results in the closing of a Na+/Ca2+ channel leading to hyperpolarization of the cell.

Cyclic AMP is a Second Messenger Used by One Class of G Proteins

Major pathways by which G-protein-linked cell-surface receptors generate small intracellular mediators.

cAMP Synthesis

Many G Proteins Use Inositol Triphosphate and Diacylglycerol As Second Messengers

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

Regulated Function Platelet activation Muscle contraction Insulin secretion Amylase secretion Glycogen degradation Antibody production Target Tissue Blood platelets Smooth muscle Pancreas, endocrine Pancreas, endocrine Liver B lymphocytes Messenger Thrombin Acethlcholine Acetylcholine Acetylcholine Antidiuretic hormone Foreign antigens

Calcium Release Following Fertilization of Animal Eggs

Fig. 5 Transient Increase in free Ca2+ concentration that occurs in an egg cell immediately after fertilization

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 the egg. 2. Egg activation- involves the resumption of many metabolic processes, reorganization of the internal contents of the egg, and other events that initiate the process of embryonic development.

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

Fig 5. The Action of Nitric Oxide on Blood Vessels. The binding of acetylcholine to endothelial cells triggers the production of nitric oxide, which diffuses into the adjacent smooth muscle cells and stimulates guanylyl cyclase, thereby leading to muscle relaxation

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 thereby altered. 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 the relative activities of the kinase and the phosphatase

Fig. 2. Protein phosphorylation reactions that are coupled in series can act as a biological 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 elevates the cyclic AMP content in the liver cell. This activates a cyclic AMP dependent protein kinase, which phosphorylates a kinase that in turn switches on the glycogen degrading enzyme phosphorylase. Hence glycogen is converted to glucose which can enter the blood 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 the glucose 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 is provided with the required energy

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

Receptor Tyrosine Kinases Aggregate and Undergo Autophosphorylation -many receptor tyrosine kinases trigger a chain of signal transduction events inside the the cell that ultimately lead to: a) cell growth b) 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

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

Receptor Tyrosine Kinases Initiate a Signal Transduction Cascade Involving 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 signal is sometimes called a mitogen, hence the name of the kinase) AP-1 - a transcription factor (appears to stimulate production of proteins needed for cells to grow and divide)

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

Growth Factor as Messengers

Growth Factors - present within serum and members of various classes of proteins Table 10. Examples of Growth Factor Families
Growth Factor Epidermal Growth Factor (EFG) Transforming growth factor(TGF-) Target Cells Wide variety of epithelial and mesenchymal cells Same as EGF Type of Receptor Complex Tyrosine kinase Tyrosine kinase

Platelet-derived growth factor (PDGF)

Transforming growth factor(TGF-) Fibroblast growth factor Interleukin-2 (IL-2)

Mesenchyme, smooth muscle, trophoblast

Fibroblastic cells Mesenchyme, fibroblasts, many other cell types Cytotoxic T-lymphocytes

Tyrosine kinase
Serine-threonine kinase Tyrosine kinase Complex of three subunits

*Disrupting of Growth Factor signaling through receptor tyrosine kinases can have dramatic effects on embryonic development -fibroblast growth factors (FGFs) and fibroblast growth factor receptors (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 mesoderm Mesoderm 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 negative mutations = 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 as achondroplasia. (Heterozygous individuals have abnormal bone growth in which the long bones suffer from abnormally slow ossification)

Cell Signals and Programmed Cell Death

-cell signaling also regulates APOPTOSIS -different from another cell death known as necrosis(which sometimes follows massive tissue injury) Differences: NECROSIS involves the swelling and rupture of the injured cells APOPTOSIS involves specific events that leads to the dismantling of the internal contents of the cell and affected cell is engulfed by other nearby cells that act as scavengers to remove the resulting cellular debris. - key event in many biological processes (eg. Removal of the webbing between digits(fingers and toes) during the development of hands and feet the resorption of the tail of tadpoles when they undergo metamorphosis, and the pruning of neurons that occurs in human infants during the first few months of life as connections mature within the developing brain. ) - in adult humans, millions of cells such as blood cells die every minute.

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

Adrenergic Hormones and Receptors are a good example of endocrine regulation

Table 10. 2 Examples of Cells Functions Regulated by cAMP

Regulated Functions Glycogen degradation Fatty acid production Heart rate, blood pressure Water reabsorption Bone resorption Target Tissue Muscle, liver adipose cardiovascular kidney bone Hormone Epinephrine Epinephrine Epinephrine Antidiuretic hormone Parathyroid hormone

Convergence, divergence and crosstalk among Signaling pathways

Signals from a variety of unrelated receptors each binding to its own ligand, can converge to activate a common effector such as Ras or Raf Signals from the same ligand, such as EGF or insulin, can diverge to 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