Cell Signaling Flashcards

Question

what type of molecules are cell surface receptors for?

Answer 1

Molecules that are too large or too hydrophilic Cannot cross the plasma membrane of the target cells → needs to rely on receptors on the surface of the target cell to relay message across the plasma membrane

Answer 2

Molecules that are small enough or hydrophobic enough Pass through the plasma membrane and into the cytosol of the target cell, where they can bind to intracellular receptor proteins

Answer 3

acetylcholine (neurotransmitter that binds to similar receptors of different target cells and induce difference responses)

Answer 4

Acetylcholine binding to heart pacemaker cell → decreased rate of firing Acetylcholine binding to salivary gland cell → secretion of serous saliva Acetylcholine binding to skeletal muscle cell → contraction of muscle

Answer 5

to survive to grow to differentiate

Answer 6

Extracellular signals work in combinations to regulate cellular behavior

Answer 7

If deprived of the necessary survival signals, most cells undergo apoptosis

Answer 8

Extracellular signals can act rapidly or slowly

Answer 9

processes that do not involve changes in gene expression ie. Changes in cell movement secretion metabolism (seconds to minutes)

Answer 10

processes that involve changes in gene expression and new protein synthesis ie. cell differentiation increased cell growth and division (minutes to hours)

Answer 11

the ligands that INITIATE cellular signaling by binding to receptors

Answer 12

chemical nature: determines how the ligands interact with their receptors and how they are transported in the body distance of action: how far the ligand travels to reach their target cells

Answer 13

chemical nature: determines how the ligands interact with their receptors and how they are transported in the body main categories: - small molecules (ie. amino acids, nucleotides) - steroid hormones (ie. cortisol, estrogen, testosterone) - lipids

Answer 14

distance of action: how far the ligand travels to reach their target cells types of distances: - endocrine signaling - paracrine signaling

Answer 15

the ligand (usually a HORMONE) is secreted into the bloodstream and travels over LONG distances to reach the target cells in DISTANT parts of the body ie. insulin, thyroid hormones

Answer 16

paracrine signals act on NEARBY target cells within the same tissue or local area; the ligands are usually secreted into the extracellular fluid and diffuse over SHORT distances to bind to receptors on neighboring cells ie. EGF, NO

Answer 17

Effector proteins: the targets of signaling pathways that execute the cellular response - can be categorized by their functions in the cell and they are often specific to the signaling pathway that is being activated different types: metabolic enzymes, cytoskeletal proteins pathway-specific examples: G protein coupled receptors pathway (GPCR), receptor tyrosine kinase pathway (RTK), PI3K pathway

Answer 18

the small INTRACELLULAR signaling molecules generated by target enzymes that relay signals from the cell surface receptors to intracellular targets to help propagate and amplify the signal within the cell; they are produced/released in response to the activation of cell surface receptors relay, amplify, integrate, distribute, and modulate via feedback an incoming signal

Answer 19

Many of the steps can be modulated via feedback by other molecules or events in the cell

Answer 20

Feedback regulation within an intracellular signaling pathways can adjust the response to an extracellular signal Helps adjust the strength, duration, and outcome of a cellular response to extracellular signals and can respond appropriately to changes in the environment or in the signaling conditions

Answer 21

positive feedback loops negative feedback loops

Answer 22

amplifies the signaling response and can lead to a stronger or prolonged response - the end product of the pathway or a downstream component STIMULATES an earlier step in the pathway ie. activation of the proteins that trigger cell division

Answer 23

dampens or limits the cellular response to avoid overactivation or prolonged signaling (serves as a way to restore homeostasis and more common than positive feedback) - when signaling pathway is activated and the cellular response reaches a certain threshold, downstream signaling proteins or transcription factors often trigger the production of molecules that inhibit upstream components of the pathway ie. receptor tyrosine kinase RTK pathway, Mitogen activated protein kinase (MAPK) pathway

Answer 24

phosphorylation vs dephosphorylation GTP vs GDP

Answer 25

Many intracellular signaling proteins act as molecular SWITCHES

Answer 26

proteins that "switch" between active and inactive states in response to specific signals - play a critical role in intracellular signaling - regulate downstream cellular processes by altering the activity, confirmation, or interaction of proteins within signaling pathways

Answer 27

phosphorylation/dephosphorylation: The addition or removal of phosphate groups that alter the protein’s conformation, activity, or interaction with other molecules; REVERSIBLE and regulated process phosphorylation often ACTIVATES the protein dephosphorylation often INACTIVATES the protein

Answer 28

enzyme that catalyzes the ADDITION of a phosphate group onto the intracellular signaling protein

Answer 29

enzyme that catalyzes the REMOVAL of the phosphate group from the intracellular signaling protein

Answer 30

GTP/GDP switches depend on the binding and hydrolysis of guanine nucleotides GTP or GDP GTP-binding protein: protein adopts an ACTIVE conformation and can interact with downstream effectors to propagate a signal GDP-binding protein: protein becomes INACTIVE and dissociates from effectors

Answer 31

based on the amino acid sequence of their CATALYTIC domains

Answer 32

serine/threonine kinases tyrosine kinases dual-specificity kinases

Answer 33

enzymes that phosphorylate the OH group of serine or threonine residues in proteins PKA (protein kinase A): activated by cAMP → regulates metabolism and gene transcription PKC: activated by diacylglycerol (DAG) and calcium ions → regulates cell growth, differentiation, and apoptosis AKT (PKB): activated in the PI3K/AKT signaling pathway → key regulator of cell survival, growth, and metabolism

Answer 34

enzymes that phosphorylate tyrosine residues in proteins subgroups: 1. nonreceptor tyrosine kinases (aka cytoplasmic tyrosine kinases) 2. receptor tyrosine kinases (aka transmembrane receptor-linked tyrosine kinases)

Answer 35

kinases that do NOT have a membrane spanning domain and instead are located in the CYTOPLASM

Answer 36

transmembrane proteins that have a kinase domain in the intracellular portion of the receptor → when ligands (ie. growth factors) bind to the extracellular domain, the receptor undergoes autophosphorylation of tyrosine residues in the cytoplasmic domain Ie. insulin receptor, EGF receptor

Answer 37

enzymes that act as BOTH tyrosine kinase AND ser/threonine kinase --> aka phosphorylates serine, threonine, or tyrosine residues in proteins Ie. MEK (MAPKK - MAP kinase kinase): a key component in the MAPK signaling pathway which regulates cell division, differentiation, and stress response

Answer 38

Small, monomeric GTPases Large, trimeric GTP-binding protein (aka G proteins)

Answer 39

single subunit proteins that bind and hydrolyze GTP to GDP (aka act as molecular switches toggling between GTP-bound on state and GDP-bound off state) - the transition between the 2 states is regulated by 2 families of proteins: 1. guanine nucleotide exchange factors (GEFs) which promote the exchange of GDP for GTP 2. GTPase-activating proteins (GAPs) which promote the hydrolysis of GTP to GDP ie. Ras protein: involved in controlling cell proliferation, differentiation, and survival ie. Rho, Rac, Cdc42: regulate the cytoskeleton and affect cell migration, shape, and division

Answer 40

G proteins consist of 3 subunits: alpha, beta, gamma relay messages from G protein coupled receptors (aka these proteins mediate the signaling pathways initiated by G protein coupled receptors GPCRs) --> when a ligand binds to a GPCR, the G protein is activated and leads to a cascade of intracellular events

Answer 41

Guanine nucleotide exchange factors (GEFs) GTPase-activating proteins (GAPs)

Answer 42

promotes the exchange of GDP for GTP, switching the protein ON --> activates monomeric GTPases to trigger downstream signaling processes

Answer 43

stimulate the hydrolysis of GTP to GDP, thus switching the protein OFF --> deactivates the monomeric GTPases and terminates the signaling and prevents prolonged activation

Answer 44

1. barbiturates and benzodiazepines (valium and ambien) 2. nicotine 3. morphine and heroin 4. curare 5. strychnine 6. capsaicin 7. menthol

Answer 45

Ion-channel-coupled receptors G-protein coupled receptors Enzyme-coupled receptors

Answer 46

type of cell surface receptors that rapidly transmits signals across synapses in the nervous system These receptors are involved in converting chemical signals (neurotransmitters) into electrical signals by regulating the flow of ions across the plasma membrane → play crucial role in synaptic transmission, muscle contraction, neuron firing, sensory perception ie. action potential with neurotransmitters: a neurotransmitter binds to ion-channel-coupled receptors on the surface of a target cell --> the receptor alters its conformation to open a channel in the target membrane → specific ions (ie. Na+, K+, Ca+) are permeable to the channel --> changes membrane potential --> generates an action potential that is passed onto the next cell

Answer 47

GPCRs form the LARGEST class of cell surface receptors: more than 700 GPCRs in humans; 1000 involved in smell alone in mice Diverse extracellular signal molecules bind GPCRs Called G-protein-coupled receptors because they signal through G proteins (guanine nucleotide-binding proteins) GPCRs are transmembrane proteins

Answer 48

transmembrane proteins

Answer 49

All GPCRs have a SIMILAR STRUCTURE: Each is made of a single polypeptide chain that treads back and forth across the lipid bilayer 7 times (hence the name) Because 7TM receptors are always associated with G proteins, they are often called G-protein-coupled receptors

Answer 50

hormone action hormone secretion neurotransmission chemotaxis exocytosis control of blood pressure embryogenesis cell growth and differentiation development smell taste vision viral infection

Answer 51

GPCR superfamily: a group of cell surface receptors that are involved in transmitting extracellular signals to the inside of the cell through interactions with G proteins and various intracellular signaling pathways examples 1. rhodopsin: a light-activated photoreceptor protein in vertebrates' eyes --> responsible for the initial step in the visual signaling pathway that allows organisms to detect light - binds to light/photons and undergoes a conformational change that activates a G protein called transducin --> triggers a cascade of intracellular events, ultimately leading to an electrical signal being generated and sent to the brain for visual processing 2. Olfactory (smell) receptors in the vertebrate nose: Responsible for detected odorants (smell molecules) in the environment and are located in the olfactory epithelium of the vertebrate nose - An odorant binds to an olfactory receptor → receptor undergoes conformational change that activates an associated G protein → leads to a signaling cascade, ultimately resulting in an electrical signal generated that the brain interprets as a smell

Answer 52

Activated by the binding of epinephrine or norepinephrine and involved in the fight-or-flight response

Answer 53

Both are members of the G protein coupled receptor superfamily (GPCR) and share a similar overall structural framework despite having distinct roles and different ligand binding sites 1. Both possess 7 transmembrane alpha-helices that span the plasma membrane and form a hydrophobic core than anchors the receptor in the lipid bilayer of the membrane → the arrangement of these 7 helices creates a binding pocket for ligands to interact with the receptor 2. Both have extracellular loops that interact with the ligand (recognition and binding) and intracellular loops that intact with G proteins (to propagate the signal into the cell) 3. For both, ligand binding induces a conformational change in the receptor’s structure 4. Both share highly conserved amino acid sequences within the transmembrane regions and intracellular loops

Answer 54

Composed of 3 protein subunits: alpha, beta, gamma

Answer 55

Alpha subunit: - largest subunit oo the G protein - has the ability to bind to GTP or GDP - Ga bound to GDP = INACTIVE state - Ga bound to GTP = ACTIVE state - Responsible for interacting with and activating downstream effectors

Answer 56

- Together these 2 subunits form the stable complex that helps anchor the G protein to the cell membrane and also play a role in signaling by modulating the activity of certain effectors in the cell - When Ga is in its INACTIVE state, it interacts with the Gbeta/gamma dimer to keep the G protein inactive → prevents Ga from interacting with downstream effects - The binding of GTP to Ga triggers a conformational change in the Ga subunit → Ga subunit dissociates from the Gbeta/gamma dimer, which allows both the Ga-GTP and Gbeta/gamma complexes to interact with and activate various downstream signaling pathways

Answer 57

1. The receptor protein undergoes conformational change AND… 2. Activates G protein: the alpha subunit affinity for GDP is reduced → the alpha subunit binds to GTP instead --> alpha subunit detaches from the beta/gamma complex, which is also activated

Answer 58

1. Activation of a target protein by the activated alpha subunit 2. HYDROLYSIS of GTP by the alpha subunit inactivates this subunit and causes it to dissociate from the target protein 3. Inactive alpha subunit reassembles with the beta-gamma complex to reform an inactive G protein The G protein alpha subunit controls the amount of time that the G protein stays active for The hydrolysis of GTP inactivates the alpha subunit The alpha subunit has an intrinsic GTPase activity → hydrolyzes its bound GTP to GDP The whole G protein returns to an inactive G protein

Answer 59

The alpha subunit has an intrinsic GTPase activity → hydrolyzes its bound GTP to GDP

Answer 60

when a G protein coupled receptor GPCR binds to the alpha subunit, the Ga exchanges GDP for GTP to become active --> this causes a conformational change in Ga that causes it to dissociate from the Gβγ dimer The activates Ga-GTP subunit can now interact with specific effector proteins (ie. adenylyl cyclase which produces cAMP from ATP, phospholipase C which generates 2nd messengers like IP3 and DAG, and ion channels or other enzymes) these effectors then initiate intracellular signaling cascades --> leads to cellular responses (ie. changes in metabolism, gene expression, ion flow)

Answer 61

the Ga subunit has an intrinsic GTPase activity (aka it can HYDROLYZE bound GTP into GDP and inorganic phosphate Pi) --> this hydrolysis reaction is slow so it is accelerated by GTPase-activating proteins (GAPs) which bind to Ga and enhance its GTPase activity THIS HYDROLYSIS REACTION MAKES THE ALPHA SUBUNIT INACTIVE AGAIN after GTP is hydrolyzed to GDP, the conformation of Ga changes back to its inactive form which reduces its affinity for target effector proteins --> Ga DISSOCIATES FROM THE TARGET PROTEIN

Answer 62

the inactive Ga-GDP subunit now has a high affinity for the Gbeta/gamma complex and reassociates with it --> the reformation of heterotrimeric G protein (aka Ga-GDP + Gbeta/gamma) restores the G protein to its INACTIVE STATE --> now ready to respond to another signal from an activated GPCR

Answer 63

Many G proteins activate membrane-bound enzymes that produce small messenger molecules

Answer 64

1. adenylyl cyclase (aka adenylate cyclase, adenyl cyclase) 2. phospholipase C

Answer 65

A membrane bound enzyme/protein with 2 intracellular domains that converts ATP into cAMP (aka generates cAMP) A key 2nd messenger in math signaling pathways The 2 intracellular domains: C1 (functions with C2 domain to form the active site for ATP conversion to cAMP) & C2 (works with C1 to catalyze the cyclization of ATP to cAMP) Activation: adenylate cyclase is activated by the Gas subunit of a G protein which binds to the intracellular domains and induces a conformational change to facilitates catalytic activity Inhibition: can be inhibited by Gαi proteins or by specific regulatory proteins (PKA-mediated phosphorylation)

Answer 66

A membrane bound enzyme that generates small molecules inositol triphosphate IP3 and diacylglycerol DAG (which are second messengers)

Answer 67

the EXTRACELLULAR signals that activated the target enzymes in the first place

Answer 68

cAMP, cGMP, calcium ion, IP3, DAG

Answer 69

adenylyl cyclase

Answer 70

1. Epinephrine binds to the beta-adrenergic receptor 2. The beta-adrenergic receptor is activated 3. The activated beta-adrenergic receptor activates adenylate cyclase 4. Adenylate cyclase produces cAMP 5. Undergoes the epinephrine signaling pathway (ie. stimulates glycogen breakdown in skeletal muscle cells 1. binding of epinephrine: Epinephrine binds to the beta-adrenergic receptor located on the plasma membrane of target cells --> binding induces a conformational change in the receptor and activates it 2. activation of G protein: The activated beta-adrenergic receptor acts as a guanine nucleotide exchange factor (GEF) and interacts with a heterotrimeric G protein --> causing the alpha subunit (Gαs) of the G protein to exchange GDP for GTP --> The activated Gαs-GTP dissociates from the β and γ subunits (Gβγ) 3. activation of adenylyl cyclase: The Gαs-GTP subunit binds to and activates adenylyl cyclase 4. production of cAMP: Adenylyl cyclase catalyzes the conversion of ATP to cAMP --> cAMP levels rapidly increase in the cytosol 5. Activation of Protein Kinase A (PKA): cAMP binds to the regulatory subunits of protein kinase A (PKA), causing them to dissociate from the catalytic subunits --> catalytic subunits of PKA are now active 6. phosphorylation of Target Proteins: activated PKA phosphorylates phosphorylase kinase which activates glycogen phosphorylase which catalyzes the breakdown of glycogen --> glucose-1-phosphate --> glucose 7. cellular response: the breakdown of glycogen provides rapid energy for muscle contraction during fight or flight response 8. signal termination: Gαs hydrolyzes GTP to GDP using its intrinsic GTPase activity enhances by GAPs; cAMP is degraded to AMP by phosphodiesterase (PDE); beta-adrenergic receptor is desensitized through phosphorylation by GPCR kinases (GRKs) and binding of arrestin

Answer 71

a G-protein-coupled receptor (GPCR) that mediates the cellular response to epinephrine (adrenaline) When epinephrine binds to this receptor, it triggers a signaling cascade that leads to the breakdown of glycogen in skeletal muscle cells, providing energy for rapid physical activity (plays a role in fight-or-flight response)

Answer 72

a macromolecule made up of three subunits, at least one of which is different from the other two

Answer 73

Gas is the alpha subunit of the G protein responsible for activating adenylyl cyclase (Gas is the GTP form of GDP)

Answer 74

cAMP stimulates the phosphorylation of many target proteins by activating protein kinase A (PKA) `

Answer 75

a cAMP dependent protein kinase (aka it is activated by second messenger cAMP) whose primary function is to PHOSPHORYLATE TARGET PROTEINS, and thus altering their activity → leads to different cellular effects (ie. metabolic regulation, gene expression, ion channel regulation, cell growth and differentiation) Activation: cAMP levels in the cell increase due to the activation of adenylyl cyclase by Gas → cAMP binds to the regulatory subunits of PKA and each regulatory subunit binds to cAMP and causes a conformational change → the regulatory subunits dissociate from the catalytic subunits → the free catalytic subunits are now active and can phosphorylate target proteins

Answer 76

1. extracellular signal molecule: epinephrine --> target tissue: heart --> major response: increase in heart rate and force of contraction 2. extracellular signal molecule: epinephrine --> target tissue: skeletal muscle --> glycogen breakdown 3. extracellular signal molecule: epinephrine, glucagon --> target tissue: fat --> major response: fat breakdown 4. extracellular signal molecule: adrenocorticotropic hormone (ACTH) --> target tissue: adrenal gland --> cortisol secretion - although all these examples of signal molecules above are hormones, some responses to local mediators and neurotransmitters are also mediated by cAMP

Answer 77

1. A rise in intracellular cAMP activates PKA 2. The activated PKA enters the nucleus and phosphorylates specific transcription regulators 3. Once transcription regulators are phosphorylated, these proteins stimulate the transcription of a whole set of target genes

Answer 78

proteins that control the expression of specific genes by binding to DNA sequences in the promoter or enhancer regions of a gene → play a key role in turning genes “on” or “off” and influence cellular functions

Answer 79

Galpha subunit has an intrinsic GTPase activity that HYDROLYZES bound GTP to GDP and Pi This hydrolysis of GTP → GDP + Pi is SLOW but is made quicker with the help of GTPase-activating proteins (GAPs) --> as a result, activation of adenylate cyclase is terminated

Answer 80

the enzyme that hydrolyzes GTP to GDP and inorganic phosphate GTP --> GDP + Pi

Answer 81

1. signal molecule: vasopressin (a peptide hormone) --> target tissue: liver --> major response: glycogen breakdown 2. signal molecule: acetylcholine --> target tissue: pancreas --> major response: secretion of amylase (a digestive enzyme) 3. signal molecule: acetylcholine --> target tissue: skeletal muscle --> major response: muscle contraction 4. signal molecule: thrombin (a proteolytic enzyme) --> target tissue: blood platelets --> major response: aggregation

Answer 82

1. Activation of GPCR → Activation of Gq protein. 2. Gq protein activation → Activation of phospholipase C (PLC). 3. PLC cleaves PIP2 → Produces IP3 and DAG. 4. IP3 diffuses to the ER, leading to Ca²⁺ release into the cytosol. 5. DAG remains in the plasma membrane and, together with Ca²⁺, activates PKC. 6. PKC activation → Phosphorylation of target proteins, leading to cellular responses

Answer 83

PKCs are serine/threonine kinases ⇒ aka they PHOSPHORYLATES serine or threonine residues in target proteins, altering the target proteins’ activity, location or interaction → affects cellular behavior

Answer 84

inositol 1,4,5-triphosphate: a WATER-SOLUBLE molecule consisting of an inositol ring with three phosphate groups attached at positions 1, 4, and 5 --> Since it is water-soluble ⇒ hydrophilic, it diffuses away from the membrane and goes to the endoplasmic reticulum (ER) Function: releases Ca2+ ions from the ER IP3 binds to IP3 receptors of ligand-gated calcium channels on the ER membrane → these channels open and allow Ca2+ to flow from the ER into the cytosol → increase in Ca2+ concentration in the cytosol which is a crucial signal that can trigger various cellular processes Ca2+ also serves as another 2nd messenger than can activate various calcium-dependent proteins and enzymes (ie. calmodulin, calcium-dependent kinases)

Answer 85

diacylglycerol: a HYDROPHOBIC molecule composed of a glycerol backbone bound to two fatty acid chains --> Since DAG is hydrophobic, it stays embedded in the plasma membrane Function: activation of protein kinase C (PKC) DAG works together with the released Ca2+ from the ER to activate protein kinase C: when DAG binds to PKC and CA2+ levels rise in the cytosol, PKC is activated at the plasma membrane → activated PKC phosphorylates serine and threonine residues in various target proteins, changing their activity, localization, and interactions → PKC regulates many cellular processes (ie. cell growth, differentiation, apoptosis, immune response)

Answer 86

Both generated through the cleavage of PIP2 (phosphatidylinositol 4,5-bisphosphate) by the enzyme phospholipase C

Answer 87

Gq --> Both the alpha subunit and the beta-gamma complex of the G protein Gq are involved in activating phospholipase C

Answer 88

The concentration of free Ca2+ in the cytosol of an unstimulated cell is kept low: 10-7M → thus transient increases in Ca2+ content produced by signaling events can be readily detected by the cell Ca2+ binds tightly to proteins and induces STRUCTURAL conformational changes in proteins

Answer 89

use special dyes that bind to Ca 2+

Answer 90

Fura-2-acetoxymethyl ester (fura-2 AM): a MEMBRANE-PERMEABLE, non-invasive derivative of the radiometric calcium indicator fura-2 → a calcium sensitive fluorescent radiometric dye 1. Fura-2 AM crosses the cell membrane freely because of the addition of the AM (acetoxymethyl ester) group which makes it lipophilic (fat-soluble) 2. Once inside the cell, the intracellular esterases cleave the AM group, leaving the activated form Fura-2 --> Fura-2 is the form one that binds to Ca²⁺ and undergoes fluorescence changes --> Fura-2 molecule exhibits different fluorescence characteristics depending on whether it is bound to Ca²⁺ or not → this difference allows the measurement of intracellular calcium concentrations through fluorescence intensity ratios When Ca²⁺ binds to fura-2, the molecule undergoes a change in its excitation and emission spectra. - Ca2+ bound Fura-2 AM & Ca2+ free Fura-2 AM

Answer 91

excitation maximum: 335 nm typical excitation wavelengths used: 340 nm emission maximum: ~510 nm

Answer 92

excitation maximum: 363 nm typical excitation wavelengths used: 380 nm emission maximum: ~510 nm

Answer 93

Ratiometric measurement can provide a quantitative assessment of intracellular calcium levels based on the ratio of fluorescence intensities at two different excitation wavelengths: bound = 340nm; free = 380nm --> The fluorescence emitted at 510 nm (the emission maximum) is measured at both of these wavelengths → compare the ratio of fluorescence intensity at these 2 wavelengths to determine the intracellular calcium concentration ⇒ the ratio is directly related to the amount of Ca²⁺ present inside the cell - A higher ratio indicates a higher Ca²⁺ concentration inside the cell, and a lower ratio indicates lower calcium levels **The ratios 510 nm/340 nm and 510 nm/380 nm are directly related to the amount of intracellular Ca2+

Answer 94

The effects of Ca2+ in the cytosol are indirect by interacting with Ca2+ - responsive proteins calmodulin

Answer 95

1. A 17KDa protein with 4 Ca2+ binding sites: 2 Ca2+ binding sites (aka EF hand motifs) in each of the globular ends of the protein 2. Serves as a Ca2+ sensor in nearly all eukaryotic cells ^^ because calmodulin DIRECTLY responds to changes in intracellular Ca2+ concentrations 3. When the cytoplasmic Ca2+ level is raised above 500 nM, the binding of Ca2+ activates CaM -- Ca2+ ions bind to the EF hand domains in calmodulin → causes conformational change that activates the protein and allows it to interact with its target proteins (ie. protein kinases, phosphatases) 4. CaM a member of the EF hand protein family

Answer 96

a helix-loop-helix structural domain that is the binding site of Ca2+ in many calcium-sending proteins --> Each EF hand can bind 1 Ca2+ ion ⇒ Calmodulin can bind a total of 4 Ca2+ ions (2 at each of the globular ends of the proteins)

Answer 97

500nM --> When the cytoplasmic Ca2+ level is raised above 500 nM, the binding of Ca2+ activates CaM

Answer 98

definition: a group of proteins that share a common structural motif called the EF hand structure: EF hand motif is composed of… 2 alpha helices (E helix and F helix) connected by a loop region (calcium-binding loop) which contains conserved amino acid residues that coordinate the binding of a Ca2+ ion - E helix: positioned BEFORE the loop the binds and calcium ion & plays a structural role to help stabilize the conformation of the motif - F helix: positioned AFTER the loop and works with E helix to create the helix-loop-helix structure - Calcium-binding loop: typically contains 12 residues with specific positions coordinating the binding of a single Ca2+ ion activation: upon binding Ca2+, EF hand proteins undergo a conformational change that exposes hydrophobic regions or alter their surface properties to interact with other proteins or target molecules

Answer 99

the plasma membrane Ca2+ ATPase the calmodulin-dependent protein kinase (CaM kinase)

Answer 100

CaM kinases: a class of serine/threonine protein kinases activated by the Ca2+/calmodulin complex (and an important class of targets for calmodulin) Function of activated CaM kinases: phosphorylate specific serine and threonine residues in target proteins

Answer 101

an enzyme that catalyzes the transfer of a phosphate group from ATP to a specified molecule

Answer 102

Plasma membrane Ca2+ ATPase: a pump that actively transports (aka uses ATP hydrolysis) Ca2+ ions out of the cytosol (either out of the cytosol or into intracellular stores - ER) Function: helps regulate intracellular Ca2+ levels by returning the cytosolic Ca2+ concentration to resting levels after a signaling event

Answer 103

1. Ca2+ increases → Ca2+ binds to CaM - Ca2+ levels in the cytosol rise during to an extracellular signal - The Ca2+ binding to calmodulin changes calmodulin’s shape to enable target protein interaction 2. The activated CaM complex with Ca2+ binds to CaM kinases → the CaM kinases are activated - Binding induces conformational changes in CaM kinase, activating its kinase domain 3. The activated CaM kinases phosphorylate selected proteins

Answer 104

definition: transmembrane proteins that display ligand-binding domains on the OUTER surface of the plasma membrane - aka a major class of cell-surface receptors that, when activated by ligand binding, either act as enzymes themselves or associate with enzymes to mediate intracellular signaling ie. receptor tyrosine kinases (RTKs)

Answer 105

Usually have only 1 TRANSMEMBRANE segment which spans the lipid bilayer as a SINGLE alpha helix (aka crosses the cell membrane only once) Extracellular domain: binds the signal molecule (aka ligand) Transmembrane domain: anchors the receptor to the plasma membrane Intracellular domain: contains or associates with enzymatic activity (Acts as a tyrosine kinase which catalyzes the transfer of phosphate from ATP to the amino acid tyrosine)

Answer 106

An enzyme itself (have their own enzyme activity) OR... Forms a complex with another protein that acts as an enzyme

Answer 107

the LARGEST class of enzyme-coupled receptors that consists of receptors with a cytoplasmic domain that functions as a tyrosine kinase

Answer 108

MAP kinase signaling pathway

Answer 109

EGFR: epidermal growth factor receptor Insulin receptor: Insulin receptor PDGFR: platelet-derived growth factor receptor VEGFR: vascular endothelial growth factor receptor FGFR: fibroblast growth factor receptor NGR: nerve growth factor receptor

Answer 110

Adaptor protein binding: An adaptor protein (ie. Grb2) docks on a specific phosphotyrosine on the activated RTK via its SH2 domain Recruitment of Ras-GEF: The adaptor protein recruits a guanine nucleotide exchange factor (GEF) specific for Ras aka Ras-GEF GDP-GTP exchange: Ras-GEF catalyzes the exchange of GDP for GTP on the Ras protein → activating Ras Activated Ras: Ras which is now bound to GTP activates downstream signaling pathways (ie. the MAP kinase (MAPK) cascade, which regulates gene expression and cellular processes)

Answer 111

Each phosphorylated tyrosine serves as a specific docking site for a different intracellular signaling protein

Answer 112

Src homology 2 (SH2) domain: protein interaction motifs on intracellular signaling proteins that recognizes and binds to specific phosphorylated tyrosines on the cytosolic tail of an activated RTK or on another intracellular signaling protein

Answer 113

Adaptor protein: a types of intracellular signaling molecule that facilitates the interaction between different proteins in a signaling pathway (typically do not have enzymatic activity but instead act as molecule bridges to help organize signaling complexes and ensuring the correct proteins are brought into proximity for signaling) ie. Grb2

Answer 114

Ras guanine nucleotide exchange factor (Ras-GEF) recruited by the adaptor protein Ras-GEF: stimulates Ras to exchange its bound GDP for GTP

Answer 115

Mitogen: extracellular signal molecules that stimulate cell proliferation and bind to RTK

Answer 116

Activated Ras activates a MAP kinase signaling pathway

Answer 117

MAPK (mitogen activated protein kinase): a serine/threonine-specific protein kinase that regulates proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis Found only in EUKARYOTES RAF: (the final kinase in the pathway) activated by Ras-GTP; phosphorylates and activates MEK MEK: activated by RAF; phosphorylates and activates MAPK MAPK: (the final kinase in the pathway) activated by MEK; translocates to the nucleus and activates various transcription factors

Answer 118

ERK (MAPK): extracellular signal regulated kinase Involved in cell proliferation, survival, and differentiation SAPKs (JNKs): stress-activated protein kinase (c-Jun NH2-terminal kinase, Jun kinase) Involved in regulating apoptosis, stress responses, and inflammatory processes P38 MAPKs Regulate inflammation, cell differentiation, and apoptosis

Answer 119

1. Activation of RTKs (Receptor Tyrosine Kinases) 2. recruitment of adaptor protein3 3. activation of Ras 4. activation of Raf 5. activation of MEK 6. activation of MAPK 7. termination of the signaling

Answer 120

MKKK: MAP kinase kinase kinase MEKK: MAP/ERK kinase kinase MKK: MAP kinase kinase MEK: MAPK/ERK kinase ERK: extracellular signal regulated kinase MAPK: mitogen activated kinase

Answer 121

EGFR is an example of a RTK follows the RTK pathway where EGFR --> ERK (MAPK) - The prototype of the ErbB (HER) family receptor tyrosine kinases (RTKs) - EGFR regulates cell growth and differentiation and are implicated in many human cancers

Answer 122

1. Insulin-like growth factor-1 (IGF-1) activates an RTK (ie. IGF-1-receptor), which recruits and activates PI3-kinase 2. PI3-kinase then phosphorylates an inositol phospholipid (in the cytosolic side of the plasma membrane) 3. The phosphorylated inositol phospholipid attracts intracellular signaling proteins (ie. AKT; in this Fig, here called protein kinase 1) that have a special domain that recognizes it 4. Akt (protein kinase B) is activated at the membrane by phosphorylation by protein kinases 1 & 2 5. The activated AKT is released from the plasma membrane and phosphorylates downstream proteins on specific serines and threonines → promote cell growth, cell survival

Answer 123

AKT stimulates cells to grow in size by activating the serine/threonine kinase TOR The activated AKT (PKB) phosphorylates and inactivates (INHIBITS) proteins that promote apoptosis TOR is activated TOR (Ser/Thr kinase): stimulate cell growth by enhancing protein synthesis and inhibiting protein degradation

Answer 124

a Ser/Thr kinase that stimulates cell growth by enhancing protein synthesis and inhibiting protein degradation

Answer 125

an anticancer drug that inhibits Tor (Target of Rapamycin)

Answer 126

an example of a protein kinase inhibitor acting as an anticancer drug treats chronic myeloid leukemia CML by specifically INHIBITING the BCR-ABL kinase that is found on the Philadelphia chr (Ph) which carries the BCR-ABL fusion gene --> the BCR-ABL fusion gene encodes for the oncogenic BCR-ABL kinase (which drives the uncontrolled proliferation of white blood cells in CML)