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Glial fibrillary acidic protein: Glial cells that support neurons #130 в контекст | | |
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Cytokeratins: Epithelial cells express more than 30 dis- #132 в контекст | | |
tinct varieties with distinct patterns of expression in different lineages (e.g., lung versus gastrointestinal epithelia). These can serve as histochemical markers for various epithelia #133 в контекст | | |
Intermediate filaments are found predominantly in a ropelike polymerized form and primarily serve to impart tensile strength and allow cells to bear mechani- cal stress. The nuclear membrane lamins are important not only for maintaining nuclear morphology but also for regulating nuclear gene transcription. The critical roles of lamins is emphasized by rare but fascinating disorders caused by lamin mutations, which range from certain forms of muscular dystrophy to progeria, a disease of premature aging. Intermediate filaments also form the major structural proteins of epidermis and hair. #134 в контекст | | |
Microtubules are 25-nm-thick fibrils composed of nonco- valently polymerized dimers of α- and β-tubulin arrayed in constantly elongating or shrinking hollow tubes with a defined polarity; the ends are designated “+” or “−.” The “−” end is typically embedded in a microtubule orga- nizing center (MTOC or centrosome) near the nucleus where it is associated with paired centrioles, while the “+” end elongates or recedes in response to various stimuli by the addition or subtraction of tubulin dimers. Microtubules are involved in several important cellular functions: #135 в контекст | | |
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Support cables for “molecular motor” proteins that allow the movement of vesicles and organelles around cells. Kinesins are the motors for anterograde (− to +) transport, whereas dyneins move cargo in a retrograde direction (+ to −). #138 в контекст | | |
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The mechanical support for sister chromatid separa- tion during mitosis #140 в контекст | | |
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The core of primary cilia, single nonmotile projections on nucleated cells that help regulate proliferation and differentiation #142 в контекст | | |
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The core of motile cilia (e.g., in bronchial epithelium) or flagella (in sperm) #144 в контекст | | |
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Cells interact and communicate with one another by forming junctions that provide mechanical links and enable surface receptors to recognize ligands on other cells. Cell junctions are organized into three basic types (Fig. 1.9): #146 в контекст | | |
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Occluding junctions (tight junctions) seal adjacent cells together to create a continuous barrier that restricts the paracellular (between cells) movement of ions and other molecules. Viewed en face, occluding junctions form a tight meshlike network of macromolecular contacts between neighboring cells. The complexes that mediate these cell–cell interactions are composed of multiple proteins, including occludin and claudin. In addition to being a high-resistance barrier to solute movement, occluding junctions also maintain cellular polarity by forming the boundary between apical and basolateral domains of cells. Significantly, these junctions (as well as the desmosomes described later) are dynamic struc- tures that can dissociate and reform as required to facili- tate epithelial proliferation or inflammatory cell migration. #148 в контекст | | |
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Anchoring junctions (desmosomes) mechanically attach cells—and their intracellular cytoskeletons—to other cells or to the ECM. When the adhesion focus is between cells, and is small and rivetlike, it is designated a spot desmosome. When such a focus attaches the cell to the ECM, it is called a hemidesmosome. Similar adhesion domains can also occur as broad bands between cells, where they are denoted as belt desmosomes. Cell–cell des- mosomal junctions are formed by the homotypic asso- ciation of transmembrane glycoproteins called cadherins. #150 в контекст | | |
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In spot desmosomes, the cadherins are linked to intracellular intermediate filaments and allow extra- cellular forces to be mechanically communicated (and dissipated) over multiple cells. #152 в контекст | | |
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In belt desmosomes, the transmembrane adhesion molecules are associated with intracellular actin microfilaments, by which they can influence cell shape and/or motility. #154 в контекст | | |
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In hemidesmosomes, the transmembrane connector proteins are called integrins; like cadherins, these attach to intracellular intermediate filaments, and thus they functionally link the cytoskeleton to the ECM. Focal adhesion complexes are large macromolecu- lar complexes that localize at hemidesmosomes, and include proteins that can generate intracellular signals when cells are subjected to increased shear stress, for example, endothelium in the bloodstream, or cardiac myocytes in a failing heart. #156 в контекст | | |
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Communicating junctions (gap junctions) mediate the passage of chemical or electrical signals from one cell to another. The junction consists of a dense planar array of 1.5- to 2-nm pores (called connexons) formed by hex- amers of transmembrane protein connexins. These pores permit the passage of ions, nucleotides, sugars, amino acids, vitamins, and other small molecules; the perme- ability of the junction is rapidly reduced by lowered intracellular pH or increased intracellular calcium. Gap junctions play a critical role in cell–cell communi- cation; in cardiac myocytes, for example, cell-to-cell #158 в контекст | | |
calcium fluxes through gap junctions allowing the myocardium to behave as a functional syncytium capable of coordinated waves of contraction—the beating of the heart. #159 в контекст | | |
Biosynthetic Machinery: Endoplasmic Reticulum and Golgi Apparatus #160 в контекст | | |
The structural proteins and enzymes of the cell are con- stantly renewed by a balance between ongoing synthesis and intracellular degradation. The endoplasmic reticulum (ER) is the site of synthesis of all transmembrane proteins and lipids needed for the assembly of plasma membrane and cellular organelles, including the ER itself. It is also the initial site of synthesis of all molecules destined for export out of the cell. The ER is organized into a mesh- like interconnected maze of branching tubes and flattened lamellae forming a continuous sheet around a single lumen that is topologically contiguous with the extracellular envi- ronment. The ER is composed of distinct domains that are distinguished by the presence or absence of ribosomes (Fig. 1.6). #161 в контекст | | |
Rough ER (RER): Membrane-bound ribosomes on the cytosolic face of the RER translate mRNA into proteins that are extruded into the ER lumen or become inte- grated into the ER membrane. This process is directed by specific signal sequences on the N-termini of nascent proteins. Proteins insert into the ER fold and must fold properly in order to assume a functional conformation and assemble into higher order complexes. Proper folding of the extracellular domains of many proteins involves the formation of disulfide bonds. A number of inherited disorders, including many cases of familial hypercholes- terolemia (Chapter 6), are cause by mutations that disrupt disulfide bond formation. In addition, N-linked oligosac- charides (sugar moieties attached to asparagine residues) are added in the ER. Chaperone molecules retain proteins in the ER until these modifications are complete and the proper conformation is achieved. If a protein fails to fold and assemble into complexes appropriately, it is retained and degraded within the ER. Moreover, excess accu- mulation of misfolded proteins—exceeding the capac- ity of the ER to edit and degrade them—leads to the ER stress response (also called the unfolded protein response or the UPR), which triggers cell death through apoptosis (Chapter 2). #162 в контекст | | |
As an example of the importance of the ER editing func- tion, the disease cystic fibrosis most commonly results from misfolding of the CFTR membrane transporter protein. In cystic fibrosis, the most common mutation in the CFTR gene results in the loss of a single amino acid residue (phe- nylalanine 508), leading in turn to misfolding, ER retention, and degradation of the CFTR protein. The loss of CFTR function leads to abnormal epithelial chloride transport, hyperviscous bronchial secretions and recurrent airway infections (Chapter 7). #163 в контекст | | |
Golgi apparatus: From the RER, proteins and lipids des- tined for other organelles or for extracellular export are shuttled into the Golgi apparatus. This organelle consists of stacked cisternae that progressively modify proteins in an orderly fashion from cis (near the ER) to trans (near the plasma membrane); macromolecules are shuttled between the various cisternae within membrane-bound vesicles. As molecules move from cis to trans, the N-linked oligosac- charides originally added to proteins in the ER are pruned and further modified in a stepwise fashion; O-linked oli- gosaccharides (sugar moieties linked to serine or threo- nine) are also appended. Some of this glycosylation is important in directing molecules to lysosomes (via the mannose-6-phosphate receptor); other glycosylation adducts may be important for cell–cell or cell–matrix inter- actions, or for clearing senescent cells (e.g., platelets and red cells). In addition to the stepwise glycosylation of lipids and proteins, the cis Golgi network is where proteins are recycled back to the ER, and the trans Golgi network is where proteins and lipids are dispatched to other organ- elles (including the plasma membrane), or to secretory vesicles destined for extracellular release. The Golgi complex is especially prominent in cells specialized for secretion, including goblet cells of the intestine, bronchial epithelium (secreting large amounts of polysaccharide-rich mucus), and plasma cells (secreting large quantities of antibodies). #164 в контекст | | |
Smooth ER (SER): The SER in most cells is relatively sparse, forming the transition zone from RER to transport vesicles moving to the Golgi. However, in cells that syn- thesize steroid hormones (e.g., in the gonads or adrenals), or that catabolize lipid-soluble molecules (e.g., in the liver), the SER may be particularly conspicuous. Indeed, repeated exposure to compounds that are metabolized by the SER (e.g., phenobarbital, which is catabolized by the cyto- chrome P-450 system) leads to a reactive hyperplasia of the SER. The SER also is responsible for sequestering intracel- lular calcium; subsequent release from the SER into the cytosol can mediate a number of responses to extracellular signals. In addition, in muscle cells, a specialized SER called the sarcoplasmic reticulum is responsible for the cycli- cal release and sequestration of calcium ions that regulate muscle contraction and relaxation, respectively. #165 в контекст | | |
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As already mentioned briefly, cellular waste disposal depends on the activities of lysosomes and proteasomes (Fig. 1.10). #167 в контекст | | |
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Lysosomes are membrane-bound organelles containing roughly 40 different acid hydrolases (i.e., enzymes that function best in acidic pH ≤5), including proteases, nucleases, lipases, glycosidases, phosphatases, and sul- fatases. Lysosomal enzymes are initially synthesized in the ER lumen and then tagged with a mannose-6-phos- phate (M6P) residue within the Golgi apparatus. Such M6P-modified proteins are subsequently delivered to lysosomes through trans-Golgi vesicles that express M6P receptors. The other macromolecules destined for catabolism in the lysosomes arrive by one of three other pathways (Fig. 1.10): #169 в контекст | | |
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Material internalized by fluid-phase pinocytosis or receptor-mediated endocytosis passes from plasma membrane to early endosome to late endosome, and ultimately into the lysosome, becoming progres- sively more acidic in the process. The early endosome is the first acidic compartment encountered, whereas proteolytic enzymes only begin significant digestion #171 в контекст | | |
in the late endosome; late endosomes mature into lysosomes. #172 в контекст | | |
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Senescent organelles and large protein complexes can be shuttled into lysosomes by a process called autophagy. Through poorly understood mechanisms, obsolete organelles are corralled by a double mem- brane derived from the ER; the membrane progres- sively expands to encircle a collection of structures and forms an autophagosome, which then fuses with lysosomes where the contents are catabolized. In addition to facilitating the turnover of aged and defunct cellular constituents, autophagy also is used to preserve cell viability during nutrient depletion. The significance of autophagy in cell biology was recognized by the award of the 2016 Nobel Prize to Yoshinori Ohsumi for his discoveries relating to the mechanism of autophagy. This topic is discussed in more detail in Chapter 2. #174 в контекст | | |
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Phagocytosis of microorganisms or large fragments of matrix or debris occur primarily in professional phagocytes (macrophages and neutrophils). The material is engulfed to form a phagosome that subse- quently fuses with a lysosome. #176 в контекст | | |
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Proteasomes play an important role in degrading cytosolic proteins (Fig. 1.10); these include denatured or misfolded proteins (akin to what occurs within the ER), as well as other proteins whose levels and half-life need to be tightly regulated (e.g., transcription factors). Many (but not all) proteins destined for proteasome destruction are targeted after covalent addition of a protein called ubiq- uitin. Polyubiquitinated molecules are progressively unfolded and funneled into the polymeric proteasome complex, a cylinder containing multiple different prote- ase activities, each with its active site pointed at the hollow core. Proteasomes digest proteins into small (6–12 amino acids) fragments that can subsequently be further degraded to their constituent amino acids and recycled, or presented to immune cells in the context of major histocompatibility complex class I molecules, an important component of host immune surveillance. #178 в контекст | | |
