BIO130 Chapter 18

• Cells in multicellular organisms communicate through a large variety of extracellular chemical signals.

• In animals, hormones are carried in the blood to distant target cells, but most other extracellular signal molecules act over only a short distance. Neighbouring cells often communicate through direct cell–cell contact.

• For an extracellular signal molecule to influence a target cell it must interact with a receptor protein on or in a target cell. Each receptor protein recognizes a particular signal molecule.

• Small, hydrophobic, extracellular signal molecules, such as steroid hormones and nitric oxide, can cross the plasma membrane and activate intracellular proteins, which are usually either transcription regulators or enzymes.

• Most extracellular signal molecules cannot pass through the plasma membrane; they bind to cell-surface receptor proteins that convert (transduce) the extracellular signal into different intracellular signals, which are usually organized into signaling pathways.

• There are three main classes of cell-surface receptors: (1) ion-channel-coupled receptors, (2) G-protein-coupled receptors (GPCRs), and (3) enzyme-coupled receptors.

• GPCRs and enzyme-coupled receptors respond to extracellular signals by activating one or more intracellular signaling pathways, which, in turn, activate effector proteins that alter the behavior of the cell.

• Turning off signaling pathways is as important as turning them on. Each activated component in a signaling pathway must be subsequently inactivated or removed for the pathway to function again.

• GPCRs activate trimeric GTP-binding proteins called G proteins; these act as molecular switches, transmitting the signal onward for a short period before switching themselves off by hydrolyzing their bound GTP to GDP.

• G proteins directly regulate ion channels or enzymes in the plasma membrane. Some directly activate (or inactivate) the enzyme adenylyl cyclase, which increases (or decreases) the intracellular concentration of the small messenger molecule cyclic AMP; others directly activate the enzyme phospholipase C, which generates the small messenger molecules inositol trisphosphate (IP3) and diacylglycerol.

• IP3 opens Ca2+ channels in the membrane of the endoplasmic reticulum, releasing a flood of free Ca2+ ions into the cytosol. The Ca2+ itself acts as a second messenger, altering the activity of a wide range of Ca2+-responsive proteins. These include calmodulin, which activates various target proteins such as Ca2+/calmodulin-dependent protein kinases (CaM-kinases) .

• A rise in cyclic AMP activates protein kinase A (PKA), while Ca2+ and diacylglycerol in combination activate protein kinase C (PKC).

• PKA, PKC, and CaM-kinases phosphorylate selected signaling and effector proteins on serines and threonines, thereby altering their activity. Different cell types contain different sets of signaling and effector proteins and are therefore affected in different ways.

• Enzyme-coupled receptors have intracellular protein domains that function as enzymes or are associated with intracellular enzymes. Many enzyme-coupled receptors are receptor tyrosine kinases (RTKs), which phosphorylate themselves and selected intracellular signaling proteins on tyrosines. The phosphotyrosines on RTKs then serve as docking sites for various intracellular signaling proteins.

• Most RTKs activate the monomeric GTPase Ras, which, in turn, activates a three-protein MAP-kinase signaling module that helps relay the signal from the plasma membrane to the nucleus.

• Ras mutations stimulate cell proliferation by keeping Ras (and, consequently, the Ras–MAP kinase signaling pathway) constantly active and are a common feature of many human cancers.

• Some RTKs stimulate cell growth and cell survival by activating PI 3-kinase, which phosphorylates specific inositol phospholipids in the cytosolic leaflet of the plasma membrane lipid bilayer. This inositol phosphorylation creates lipid docking sites that attract specific signaling proteins from the cytosol, including the protein kinase Akt, which becomes active and relays the signal onward.

• Other receptors, such as Notch, have a direct pathway to the nucleus. When activated, part of the receptor migrates from the plasma membrane to the nucleus, where it regulates the transcription of specific genes.

• Plants, like animals, use enzyme-coupled cell-surface receptors to recognize the extracellular signal molecules that control their growth and development; these receptors often act by relieving the transcriptional repression of specific genes.

• Different intracellular signaling pathways interact, enabling each cell type to produce the appropriate response to a combination of extracellular signals. In the absence of such signals, most animal cells have been programmed to kill themselves by undergoing apoptosis.

• We are far from understanding how a cell integrates all of the many extracellular signals that bombard it to generate an appropriate response.

• The eukaryotic cell cycle consists of several distinct phases. In interphase, the cell grows and the nuclear DNA is replicated; in M phase, the nucleus divides (mitosis) followed by the cytoplasm (cytokinesis).

• In most cells, interphase consists of an S phase when DNA is duplicated, plus two gap phases—G1 and G2. These gap phases give proliferating cells more time to grow and prepare for S phase and M phase.

• The cell-cycle control system coordinates events of the cell cycle by sequentially and cyclically switching on and off the appropriate parts of the cell-cycle machinery.

• The cell-cycle control system depends on cyclin-dependent protein kinases (Cdks), which are cyclically activated by the binding of cyclin proteins and by phosphorylation and dephosphorylation; when activated, Cdks phosphorylate key proteins in the cell.

• Different cyclin–Cdk complexes trigger different steps of the cell cycle: M-Cdk drives the cell into mitosis; G1-Cdk drives it through G1; G1/S-Cdk and S-Cdk drive it into S phase.

• The control system also uses protein complexes, such as APC, to trigger the destruction of specific cell-cycle regulators at particular stages of the cycle.

• The cell-cycle control system can halt the cycle at specific transition points to ensure that intracellular and extracellular conditions are favorable and that each step is completed before the next is started. Some of these control mechanisms rely on Cdk inhibitors that block the activity of one or more cyclin–Cdk complexes.

• S-Cdk initiates DNA replication during S phase and helps ensure that the genome is copied only once. The cell-cycle control system can delay cell-cycle progression during G1 or S phase to prevent cells from replicating damaged DNA. It can also delay the start of M phase to ensure that DNA replication is complete.

• Centrosomes duplicate during S phase and separate during G2. Some of the microtubules that grow out of the duplicated centrosomes interact to form the mitotic spindle.

• When the nuclear envelope breaks down, the spindle microtubules capture the duplicated chromosomes and pull them in opposite directions, positioning the chromosomes at the equator of the metaphase spindle.

• The sudden separation of sister chromatids at anaphase allows the chromosomes to be pulled to opposite poles; this movement is driven by the depolymerization of spindle microtubules and by microtubuleassociated motor proteins.

• A nuclear envelope re-forms around the two sets of segregated chromosomes to form two new nuclei, thereby completing mitosis.

• In animal cells, cytokinesis is mediated by a contractile ring of actin filaments and myosin filaments, which assembles midway between the spindle poles; in plant cells, by contrast, a new cell wall forms inside the parent cell to divide the cytoplasm in two.

• In animals, extracellular signals regulate cell numbers by controlling cell survival, cell growth, and cell proliferation.

• Most animal cells require survival signals from other cells to avoid apoptosis—a form of cell suicide mediated by a proteolytic caspase cascade; this strategy helps ensure that cells survive only when and where they are needed.

• Animal cells proliferate only if stimulated by extracellular mitogens produced by other cells; mitogens release the normal intracellular brakes that block progression from G1 or G0 into S phase.

• For an organism or an organ to grow, cells must grow as well as divide; animal cell growth depends on extracellular growth factors that stimulate protein synthesis and inhibit protein degradation.

• Some extracellular signal molecules inhibit rather than promote cell survival, cell growth, or cell division.

• Cancer cells fail to obey these normal “social” controls on cell behavior and therefore outgrow, out-divide, and out-survive their normal neighbors.