Both free-living cells and cell in multicellular organisms need to communicate with their surroundings

- for multicellular organisms, cells need to both respond to signals from the environment and
    to coordinate development

- many cancers arise from breakdown in signaling pathways that control cell proliferation and survival

Signaling Molecules and Their Receptors

      Signals can act over long or short range

General forms of cell signaling

1.      Direct Cell-Cell = interaction between cell surface molecules on
        cells directly adjacent to each other, e.g. developmental responses
        - a cell knows what to become partly by sensing who its neighbors are.

2.     Endocrine = hormones produced by specialized signaling cell secreted into
        circulatory system (or in plants moved by other methods including through the
        sap), target cells widely distributed through body, e.g. stress response/
       adrenaline, or sexual development/estrogen

3.      Paracrine = local, molecule secreted by one cell acts on neighboring target cell
        e.g. nerve cells/acetylcoholine

4.    Autocrine = self, cell produces a growth factor to which it also responds,
        e.g. vertebrate immune response/growth factors
 

Each cell responds to a limited set of signals

How do cells know which signals to respond to out of the multitude they are bombarded with constantly?

Receptor proteins = proteins that detect a signal (often a change in
    concentration of a specific molecule) and thereupon initiates a response
    in a cell.

             - many are PM proteins which interact with hormones

                        e.g.neurotransmitters and other molecules in the external medium

- without a receptor for a specific signal, the cell is deaf to it - no response

- by producing limited set of receptors, cell restricts which signals it can respond to

                Steroid hormones and related signaling molecules are small hydrophobic molecules

                        e.g. testosterone,  estrogen, cortisone, thyroid hormone, vitamin D₃, retinoic acid

                        -  diffuse across PM, bind to intracellular receptors

                                    - receptor proteins expressed only in hormonally responsive cells

                                    - related members of a protein family

                        - complex acts as transcription factor to directly regulate gene expression
 

        Nitric Oxide and Carbon Monoxide

                 Both are simple gases, but act as important paracrine signaling molecules

                        e.g. nervous, immune, and circulatory systems

                        - after synthesis, diffuse out of cell and affect neighbor cells

                                - local because very unstable, break down

                        - diffuse across PM, alter activity of target enzymes

                                e.g. NO stimulates guanylyl cyclase in muscle cells, induces muscle relaxation

                                                        "            blood vessel dilation
                                                        "            blood flow to heart (e.g. nitroglycerin -> NO)
 

        Neurotransmitters

                 Small hydrophilic molecules that carry signals between neurons or
                            between neurons and other target cells (e.g. muscle) at a synapse

                       e.g. acetylcholine, dopamine, adrenaline, GABA, glutamate

                        - release signalled by arrival of action potential at nerve terminus

                        - diffuse across synaptic cleft, bind to cell surface receptor

                        - many bind to ligand-gated ion channels
 

        Peptide Hormones and Growth Factors  (see Table 13.1)

                 Peptide hormones range from a few to >100 amino acids

                        e.g. insulin, growth hormone, neuropeptides (endorphin, enkephalins),
                                    and growth factors (nerve growth factor, epidermal growth factor)

                        - bind to cell surface receptors
 

        Eicosanoids

                 A class of lipids that function in both paracrine and autocrine signaling

                        e.g. prostaglandins, leukotrienes

                        - act locally, because they are rapidly broken down

                        - bind to cell surface receptors, stimulate inflammation and smooth muscle contraction

                        - aspirin and other non-steroidal anti-inflammatories inhibit enzyme that
                                synthesizes eicosanoids from arachidonic acid

                                - inflammation and pain are reduced
 

        Plant Hormones

                A variety of small molecules or peptides that regulate plant growth,
                            development and response to environment

                        e.g. auxin (tryptophan analog), ethylene (gas), brassinolide (steroid)

                        - each hormone has multiple effects on multiple target tissues and each response is
                                regulated by multiple hormones

                                e.g. at least 5 different plant hormones regulate stem growth

                        - coordinate the responses of tissues in different parts of plant to environmental signals
 
 

Functions of Cell Surface Receptors

        A variety of different type of receptors detect signals from outside of the cell

        G Protein-Coupled Receptors

                The largest family of cell surface receptors

                        e.g. receptors for many hormones and neurotransmitters, esp. those
                                responsible for smell, sight, and touch

                - transmit signals to intracellular targets via heterotrimeric G-proteins
                            = GTP-binding proteins

                        - activity regulated by whether GTP or GDP is bound

                - receptor characterized by 7 transmembrane helices
 

        Receptor Protein-Tyrosine Kinases (RPTKs)

                The receptors for most peptide growth factors

                        - all have N-terminal extracellular ligand-binding domain,
                                single transmembrane helix, cytosolic C-terminal domain that
                                phosphorylates tyrosines of target proteins --> activates
 
 

        Cytokine Receptors

                Act in conjunction with non-receptor protein-tyrosine kinases

                        - otherwise structure similar to RPTKs, large protein family
 

        Other cell surface receptors are linked to phosphatases, protein-serine kinases, and guanylyl cyclases
 
 

Pathways of Intracellular Signal Transduction
 

     one signal binding to one receptor can cause multitude of effects on target cell

- e.g. shape, movement, metabolism, gene expression, survival

- receptor, signal transduction chain and intracellular targets can all vary from
            one type of specialized cell to another,

        e.g. different cells respond to same signal in different ways

    the cell is simultaneously sensitive to many extracellular signals, must be integrated

- simultaneous signals can result in responses which are more than just the sum
        of the effects that each signal alone would evoke

- intracellular relay systems for different signals interact

        - presence of one signal modifies responses to others

        - allows small number of signals to be used in different combinations
                to provide complex control over cell behaviour

 

    Signaling Cascades = relay chains of intracellular signaling molecules

    - receptor protein performs primary transduction step

            - receives external signal, generates new intracellular signal
 

- in cells = process by which a cell produces a response to an extracellular signal

        The cAMP Pathway

               In animals, cyclic AMP (cAMP) is an important second messenger in cellular responses
                            to hormones and odorants

                            - rarely used 2nd messenger in plants

                -  most actions of cAMP are mediated  by protein kinase A (PKA)

                            - phosphorylates both metabolic enzymes and transcription factors (e.g. CREB)

        Cyclic GMP

                Cyclic GMP (cGMP) plays a more important role as a 2nd messenger in plants, less in animals, but still important

                        - involved in visual perception by rhodopsin (a G protein-coupled receptor + retinal) in vertebrate eye  and
                                    red light perception by phytochrome in plants

                                - activation of rhodopsin by light causes decrease in cGMP via phosphodiesterase

                                        - reduced cGMP translated to nerve impulse via ion channels

                        - action also frequently mediated by activation of a cGMP-dependent protein kinase

        Phospholipids and Ca²⁺

                Ca²⁺ and phosphlipids are important second messengers in both plants and animals

                        - often activated downstream of G-protein-coupled receptors and receptor kinases

                       - hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) results in diacylglycerol (DAG) and inositol-triphosphate (IP₃)

                                - DAG and IP₃ work together to activate protein kinase C (PKC)

                                - results in release of Ca²⁺ from intracellular stores (mainly ER, except PM in electrically excitable cells)

                                - increased Ca²⁺ activates variety of proteins

                        - PIP₂ can also be phosphorylated and becomes another second messenger, PIP₃

        Ras, Raf and the MAP Kinase Pathway

                The MAP (Mitogen-Activated-Protein) kinase pathway is a chain of protein kinases activated downstream
                        of a variety of extracellular signals

                        - named for the response to signals that cause cell proliferation

                        - present in yeasts, animals, and plants

                                -  in animals, well-studied ones are coupled to growth factor receptors by the small G protein Ras

                                        - leads to activation of a MAP kinase called ERK

                                        - activated ERK phosphorylates a variety of cytosolic and nuclear proteins, including
                                            transcription factors that mediate immediate-early genes (~100) that share a common
                                            regulatory sequence = SRE, serum response element

                                - in plants, one MAP kinase pathway mediates responses to ethylene via a histidine kinase receptor complex

                        - yeast, plants, and animals all have multiple MAP kinase pathways that control distinct cellular responses

                                -  each cascade has a terminal MAP kinase, a MAP kinase kinase, and a MAP kinase kinase kinase

                                - e.g. yeast has 5 different MAP kinase cascades that regulate mating, sporulation, filamentation,
                                            cell wall remodeling, and osmolarity responses.
 

        JAK/STAT Pathway

                JAKs are a family of non-receptor tyrosine kinases that directly activate STATs = transcription factors w/SH₂ domains
 

Signaling in Development and Differentiation

        Both cell differentiation and the development of body structures are regulated by intricate pathways of
                    cell-cell signaling that coordinate the activities of individual cells

        Photoreceptor differentiation in fruit flies and vulval induction in C. elegans is regulated through
                receptor tyrosine kinase/Ras/MAP kinase pathways
 
 

Regulation of Programmed Cell Death

        Programmed cell death = a normal form of cell death characterized by apoptosis

                apotosis is characterized by cleavage of chromosomal DNA, chromatin condensation, and
                        fragmentation of the nucleus and the cell

                        - different from accidental death of  cells from acute injury

                        - active, controlled process

                programmed cell death plays a key role in both embryonic development and maintenance of adult tissues

                         - also  defense mechanism for eliminating damaged or infected cells 

                         - genes involved are very highly conserved

                        caspases = family of proteases that help carry apoptosis out

                        cell death receptors  bind signals like tumor necrosis factor (TNF) and activate caspases

        Many cells are dependent on survival signals or cell-cell contacts to suppress apoptosis

                PI3-kinase/Akt pathway = major player in promoting cell survival