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Chapter 13 Signal Transduction

Terms in this set (56)

signal transduction cascade
1. Release of a primary message as a response to a physiological circumstance
2. Reception of the primary message by a receptor, usually an integral membrane protein
3. Relay of the detection of the primary message to the cell interior by the generation of a intracellular second messenger
4. Activation of effector molecules by the second messenger that result in a physiological response
5. Termination of the signal cascade
Common Second Messengers
cyclic AMP (cAMP) and cyclic GMP (cGMP)
calcium ion
inositol 1,4,5-trisphosphate (IP3)
diacylglycerol (DAG)
Second messengers
intracellular molecules that change in concentration in response to environmental signals
-the change in concentration conveys information inside the cell
Three major classes of membrane receptors
Seven transmembrane receptors associated with heterotrimeric G-proteins
Dimeric membrane receptors that recruit protein kinases
Dimeric protein receptors that are protein kinases
Seven-transmembrane helix (7TM) receptors
change conformation in response to ligand binding and activate G proteins
mediate a host of biological functions by responding to a variety of signal molecules (ligands), including hormones, tastants, and even photons
the binding of a ligand outside the cell induces a structural change in the receptor that can be detected inside the cell
*often called G protein coupled receptors or GPCR because receptors always associated with G proteins
Biological functions mediated by 7TM receptors
Hormone action
Hormone secretion
neurotransmission
chemotaxis
exocytosis
control of blood pressure
embryogenesis
cell growth and differentiation
development
smell
taste
vision
viral infection
Pathway 1: Signal transduction by heterotrimeric G proteins
Hormone binding to a 7TM receptor iniates pathway that acts through a G protein and cAMP to activate protein kinase A
kinase
enzyme that adds a phosphate group to a protein
heterotrimeric G protein
binds to GDP (inactive) or GTP (active)
Phosphatase
protein that will remove phosphate group from a protein
epinephrine
also called adrenaline
activates beta-adrenergive receptor by binding to it which then activates a heterotrimeric G-protein
unactivated G-protein
heterotrimer consisting of an alpha subunit, bound to GDP, and beta and gamma subunits
alpha subunit
upon activation by the receptor, dissociates from the beta-gamma dimer and exchanged GDP to GTP
adenylate cyclase
integral membrane enzyme stimulated by activated G protein
activation leads to the synthesis of the second messenger, cAMP
cyclic AMP
activates protein kinase A
binding by the regulatory subunits dissociates the subunits from the complex
protein kinase A
two pairs of subunits
2 catalytic (C) subunits and 2 regulatory (R) subunits
How cAMP activates protein kinase A
Cyclic AMP activates protein kinase A. Protein kinase A consists of two pairs of subunits, 2 catalytic (C) subunits and 2 regulatory (R) subunits.

Binding of cAMP by the regulatory subunits dissociates these subunits from the complex, resulting in activation of the 2 C subunits.
serine
threonine
tyrosine
amino acids from protein residue that can be phosyphorylated
Termination of signal transduction for pathway 1: Resetting Galpha
On hydrolysis of the bound GTP by the intrinsic GTPase activity of Gα, Gα reassociates with the βγ dimer to form the heterotrimeric G protein, thereby terminating the activation of adenylate cyclase
Gα has inherent GTPase activity that cleaves the bound GTP to GDP. The Gα bound to GDP spontaneously reassociates with the βγ subunits, terminating the activity of the G protein.
Defects in Pathway 1
cholera and whooping cough are due to altered G protein activity
Cholera
an acute bacterial disease that produces life-threatening diarrhea
Choleragen
the bacterial toxin, modifies a Gαs protein such that it is trapped in the active GTP-bound form --> net result is loss of NaCl and water into the intestine
Pertussis toxin
cause of whopping cough
also modifies a G protein. In this case, the G protein, , Gαi, is trapped in the inactive form. Gαi, which normally inhibits a host of biochemical targets, is thus rendered inactive
Pathway 2: the phospholipase C reaction
the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) results in the release of calcium ions (owing to the opening of the IP3 receptor ion channels) and the activation of protein kinase C (owing to the binding of protein kinase C to free DAG in the membrane). Calcium ions bind to protein kinase C and help facilitate its activation.
The epinephrine-imitated pathway is shut down in a variety of ways
Gα has inherent GTPase activity that cleaves the bound GTP to GDP. The Gα bound to GDP spontaneously reassociates with the βγ subunits, terminating the activity of the G protein.
Cyclic AMP phosphodiesterase converts cAMP to AMP, which does not activate protein kinase A.
Epinephrine-β-adrenergic receptor interaction is reversible. Once the concentration of epinephrine falls, the receptor will no longer be active.
Receptor dimerization
A single growth-hormone molecule (blue) interacts with the extracellular domains of two receptors (red). The binding of one hormone molecule to two receptors leads to the formation of a receptor dimer. Dimerization is a key step in this signal-transduction pathway.
Janus Kinase (JAK)
The cross-phosphorylation of two molecules of JAK2 induced by receptor dimerization. The binding of growth hormone (blue) leads to growth-hormone-receptor dimerization, which brings two molecules of Janus kinase 2 (JAK2, yellow) together in such a way that each phosphorylates key residues on the other. The activated JAK2 molecules remain bound to the receptor.
contain tyrosine kinase domains within their covalent structures
Some growth factors and hormone receptors, such as the epidermal growth factor and insulin, bind to receptors that are tyrosine kinases, called receptor tyrosine kinases (RTK). Upon growth factor or hormone binding, these receptor form dimers.
receptor dimerization
leads to cross-phosphorylation and activation of the two intracellular kinase domains
phosphorylated kinases
form docking platforms for other components of the signal transduction pathway
Ras
a key component of the EGF pathway, as well as other signal transduction pathways
a member of the family of signal proteins called small G proteins or small GTPases
monomeric
active when bound to GTP and inactive when bound to GDP
regulates cell growth through serine or threonine protein kinases
Rho
reorganizes cytoskeleton through serine or threonine protein kinases
Arf
activates the ADP-ribosyltransferase of the cholera toxin A subunit; regulates vesicular trafficking pathways; activates phospholipase D
Rab
plays a key role in secretory and endocytotic pathways
Ran
functions in the transport of RNA and protein into and out of the nucleus
Insulin
secreted when blood is rich in glucose (after a meal)
Insulin signal transduction pathway
insulin receptor phsophorlyates insulin-receptor substrates
phosphorylated IRSs are adaptor proteins to convey the insulin signal
phosphoinositide-3 kinase binds IRS and then phosphorylates phosphatidylinositol 4,5-bisphophate (PIP2) to form phosphatidylinositol 3,4,5-triphosphate (PIP3)
PIP3 activates PIP3-dependent kinase, which in turn, phosphorylates andd activates the kinase AKT
AKT phosphorylates GLUT4, increasing glucose uptake by the cells, as well as enzymes that convert glucose into glycogen
action of lipid kinase in insulin signaling
phosphorylated IRS-1 and IRS-2 activate the enzyme
phosphatidylinositide 3-kinase
enzyme that converts PIP2 and PIP3
Insulin Signaling Termination
terminated by the action of phosphates
protein phosphates remove phosphates from the activated proteins in the insulin transduction pathway, terminating the insulid signal
lipid phosphatases contribute to signal termination by converting PIP3 into PIP2
Calmodulin EF hand
formed by a helix-loop-helix unit
a binding site for Ca2+ in many calcium-sensing proteins
calcium ion bound in a loop connecting two nearly perpendicular helices
common Ca2+ sensor
formation of the bcr-abl gene by translocation
in chronic myelogenous leukemia, parts of chromosomes 9 and 22 are translocated to form a new, bcr-abl fusion gene
c-abl is a protein kinase
The protein kinase encoded by the bcr-abl gene is expressed at higher levels in cells having this translocation than is that encoded by the c-abl gene in normal cells.
Gleevec is an inhibitor of c-abl.
- a drug for CML
lipids
the alpha and gamma subunits of heterotrimeric G proteins are anchored to the cell membrane by being covalently linked to this type of molecule
protein kinase C
enzyme becomes active when bound to Ca2+ and diacylglycerol
small G-protein or small GTPase
Ras is a member of this family of proteins
active when bound to GTP and inactive when bound to GDP
oncogene
a gene that leads to the transformation of susceptible cell types into cell types with cancerlike characteristics
calmodulin
protein binds to calcium ions and serves as a Ca2+ sensor in eukaryotic cells
kinases
enzymes that phosphorylate proteins
serine/threonine kinases
tyrosine kinases
what are the two major types of kinases based on their target residues?
phosphatases
enzymes that remove phosphate groups from proteins
adenylate cyclase
membrane protein catalyzes the conversion of ATP to cAMP
phopholipase C, IP3, DAG
Cleavage of PIP2 by ___________ yields the secondary messengers _______ and ________
GPCR
7TM receptors are also known as
epinephrine or adrenaline
binds to beta-andrenergic receptors
Ca2+
binding of IP3 to the IP3 receptor results in the release of _________ from the endoplasmic reticulum
insulin
insulin receptor
GLUT
The hormone is secreted when blood is rich in glucose _____________, and this hormone binds to a receptor ____________, which activates this transporter:__________.
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