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    which of the following events contributes to the termination of a signal generated by the binding of a ligand to a receptor tyrosine kinase?

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    Cell signaling by receptor

    Recent structural studies of receptor tyrosine kinases (RTKs) have revealed unexpected diversity in the mechanisms of their activation by growth factor ligands. Strategies for inducing dimerization by ligand binding are surprisingly diverse, as are mechanisms ...

    Cell. Author manuscript; available in PMC 2011 Jun 25.

    Published in final edited form as:

    Cell. 2010 Jun 25; 141(7): 1117–1134.

    doi: 10.1016/j.cell.2010.06.011

    PMCID: PMC2914105

    NIHMSID: NIHMS219829

    PMID: 20602996

    Cell signaling by receptor-tyrosine kinases

    Mark A. Lemmon and Joseph Schlessinger

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    The publisher's final edited version of this article is available at Cell

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    Abstract

    Recent structural studies of receptor tyrosine kinases (RTKs) have revealed unexpected diversity in the mechanisms of their activation by growth factor ligands. Strategies for inducing dimerization by ligand binding are surprisingly diverse, as are mechanisms that couple this event to activation of the intracellular tyrosine kinase domains. As our understanding of these details becomes increasingly sophisticated, it provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases. Much remains to be learned, however, about the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses.

    Since the discovery of the first receptor tyrosine kinase (RTK) more than a quarter of a century ago, many members of this family of cell surface receptors have emerged as key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control (Blume-Jensen and Hunter, 2001; Ullrich and Schlessinger, 1990). Humans have 58 known RTKs, which fall into twenty subfamilies (Figure 1). All RTKs have a similar molecular architecture, with a ligand-binding region in the extracellular domain, a single transmembrane helix, and a cytoplasmic region that contains the protein tyrosine kinase (TK) domain plus additional carboxy (C-) terminal and juxtamembrane regulatory regions. The overall topology of RTKs, their mechanism of activation, and key components of the intracellular signaling pathways that they trigger are highly conserved in evolution from the nematode Caenorhabditis elegans to humans, which is consistent with the key regulatory roles that they play. Furthermore, numerous diseases result from genetic changes or abnormalities that alter the activity, abundance, cellular distribution, or regulation of RTKs. Mutations in RTKs and aberrant activation of their intracellular signaling pathways have been causally linked to cancers, diabetes, inflammation, severe bone disorders, arteriosclerosis and angiogenesis. These connections have driven the development of a new generation of drugs that block or attenuate RTK activity.

    Figure 1

    Receptor tyrosine kinase families

    Human receptor tyrosine kinases (RTKs) contain 20 subfamilies, shown here schematically with the family members listed beneath each receptor. Structural domains in the extracellular regions, identified by structure determination or sequence analysis, are marked according to the key presented in Supplementary Figure 1, where all 58 RTKs in the human proteome are listed. The intracellular domains are shown as red rectangles.

    In this Review, we discuss insights into the mechanism of RTK regulation that have emerged from recent structural and functional studies. We examine prevailing concepts that underlie the activation of intracellular signaling pathways following growth factor binding to RTKs. We also consider recent systems biology approaches for understanding the complicated circuits and networks that result from the interplay among the multiple signaling pathways activated by RTKs. Finally, we describe the impact of these advances on the discovery and application of new therapies for cancers and other diseases driven by activated RTKs.

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    Mechanisms of Receptor Activation

    In general, growth factor binding activates RTKs by inducing receptor dimerization (Ullrich and Schlessinger, 1990). However, before discussing this aspect of RTK regulation, it is important to note that a subset of RTKs forms oligomers even in the absence of activating ligand. For example, the insulin receptor and IGF1-receptor are expressed on the cell surface as disulfide-linked (αβ)2 dimers (Ward et al., 2007). Binding of insulin or IGF1 induces structural changes within these dimeric receptors that stimulate tyrosine kinase activity and cell signaling. Some studies have suggested that epidermal growth factor (EGF) binds to and activates pre-existing oligomers of its receptor (Clayton et al., 2005; Gadella and Jovin, 1995), but the precise nature and size of these oligomers is not known. Moreover, there is evidence that activation of certain RTKs, such as Tie2 (an angiopoietin receptor) and Eph receptors, may require the formation of larger oligomers (Barton et al., 2006; Himanen and Nikolov, 2003).

    Whether the ‘inactive’ state is monomeric or oligomeric, activation of the receptor still requires the bound ligand to stabilize a specific relationship between individual receptor molecules in an ‘active’ dimer or oligomer. Structural studies of the extracellular regions of RTKs have provided clear views of how ligand binding can drive dimerization. In addition, the single membrane-spanning α-helix may contribute to dimerization in some cases, although the precise role is not yet clear. In the ligand-bound receptor, self-association of the extracellular region is thought to guide the intracellular domains into a dimeric conformation that activates their tyrosine kinase domains through the mechanisms discussed below. One receptor in the dimer/oligomer then phosphorylates one or more tyrosines in a neighboring RTK, and the phosphorylated receptor then serves as a site for assembly (and activation) of intracellular signaling proteins (Ullrich and Schlessinger, 1990).

    Source : www.ncbi.nlm.nih.gov

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    Final Exam Flashcards

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    Final Exam

    What are the functions of globular proteins and give an example of each?

    C5

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    1. Storage of ions and molecules (myoglobin, ferritin)

    2. Transport of ions and molecules (Hemoglobin, serotonin transporter)

    3. Defense against pathogens (antibodies, cytokines)

    4. Muscle contraction (actin, myosin)

    5. Biological catalysis (chymotrypsin, Lysozyme)

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    Explain conformation vs configuration

    C1

    Click card to see definition 👆

    Conformation is the spatial arrangement of substituent groups that are free to assume different positions in space

    Configuration is the fixed spatial arrangement of atoms

    -double bonds (geometric isomers)

    - chiral centers (stereoisomers)

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    Terms in this set (32)

    What are the functions of globular proteins and give an example of each?

    C5

    1. Storage of ions and molecules (myoglobin, ferritin)

    2. Transport of ions and molecules (Hemoglobin, serotonin transporter)

    3. Defense against pathogens (antibodies, cytokines)

    4. Muscle contraction (actin, myosin)

    5. Biological catalysis (chymotrypsin, Lysozyme)

    Explain conformation vs configuration

    C1

    Conformation is the spatial arrangement of substituent groups that are free to assume different positions in space

    Configuration is the fixed spatial arrangement of atoms

    -double bonds (geometric isomers)

    - chiral centers (stereoisomers)

    What is a chiral molecule?

    C1

    A molecule that is not superimposable on its mirror image; has no symmetry in the molecule.

    What is an achiral molecule?

    C1

    A molecule that is superimposable on its mirror image; has symmetry in the molecule.

    How many stereoisomers can a molecule with one chiral center have? (b) when it has 2 or more centers

    C1 a. 2 b. 2^n

    Many enzymes ________activation energy so that reactions can occur_________

    C1 lower; quicker

    What are the steps that form hexokinase from DNA?

    C1

    1. DNA undergoes a catalyzed reaction at the site of the hexokinase gene

    2. Transcription of DNA into complementary RNA

    3. Messenger RNA: translation of RNA on ribosome to polypeptide chain

    4. Unfolded hexokinase

    5. folding of polypeptide chain into native structure of hexokinase

    4. Catalytically active hexokinase produced

    What kind of RNA has catalytic function?

    C1 tRNA

    What type of RNA have enzymatic function

    C1 Ribozyme

    Why are the properties of water (Melting point, boiling point, heat of vaporization) much higher than other solvents

    C2

    Due to the H-bonding- it makes intraeletral bonding stronger

    What are proteins? C2

    Connected amino acid units

    name this functional group

    C2 Alcohol

    Name this functional group

    C2 Ketone

    What does it mean for a compound to be amphiphatic?

    C2

    It contains regions that are polar and regions that are nonpolar

    What happens to the surrounding water molecules when a amphiphilic substance is put into water

    C2

    Water will surround the hydrophobic tail and become highly ordered (forms a "cage" around it)

    What is a ligand?

    - it is a molecule that binds specifically and reversibly to a larger one

    -interaction is usually highly specific and can be modulated by regulators

    What are some examples of ligands?

    -hormones/ receptors

    -antigen/ antibody -substrate/enzyme

    Signal transduction is part of a cell's response to an external signal. Although signal transduction pathways can differ in their details, there are some common elements.

    Select the six statements that accurately describe signal transduction pathways:

    a) A receptor may pass on a signal by interacting with another protein or by acting as an enzyme.

    b) A ligand, such as a hormone, binds to a specific cell surface receptor on a target cell.

    c)A second messenger may carry a signal from the cell membrane to an organelle.

    d) A ligand phosphorylates protein residues, ending the signaling cascade inside the cell.

    e) Signal transduction cascades directly transmit a single stimulus to a single target.

    f) Signal transduction cascades, often involving protein kinases, amplify a signal intracellularly.

    g) Phosphatases remove phosphoryl groups from polypeptides, regulating a cell's response.

    h) A receptor changes conformation upon binding, transmitting a signal across the cell membrane

    i).A second messenger carries a signal from a tissue or organ to a target cell.

    H, F, C, B A,G

    G protein‑coupled receptors (GPCRs) transform external stimuli to intracellular signals. The G protein associated with the receptor is activated by ligand binding, regulating an enzyme that produces a second messenger. The second messenger, in turn, brings about changes within the cell.

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