test 3

Question 1

alpha G protein (active for signaling) + GTP>can activate downstream; alpha G protein+GDP (inactive); GAP to go from active alpha G to inactive and GTP/GEF to do the reverse; beta and gamma subunits dissociate from activated G-protein alpha subunit

Answer 1

GPCRs and trimeric G proteins

Question 2

these processes are for quick changes in physiology of organism, part of this is the second messengers; activity of the alpha subunit if terminated by hydrolysis of the bound GTP, which is stimulated by RGS proteins, the inactive GDP-bound alpha subunit then reassociates with beta/gamma complex>in the inactive state, the alpha subunit is bound to GDP in a complex with beta and gamma>hormone binding stimulates the release of GDP and its exchange for GTP; the activated GTP-bound alpha subunit and beta/gamma complex then dissociate from the receptor and interact with their targets

Answer 2

activation of trimeric G proteins

Question 3

activation of GPCRs can lead to the production of second messengers-properties=small molecules or ions (can rapidly diffuse), lots of molecules can be produced quickly (unlike synthesizing a new protein

Answer 3

GCPRs and second messengers

Question 4

can lead to enzyme activation, gene transcription and activation of other signaling pathways; short-lived due to break down by cAMP phosphodiesterase

Answer 4

production and degradation of cAMP

Question 5

cAMP is made when adenylyl cyclase is activated modifying regulatory subunit of protein kinase A which activates catalytic subunit allowing it to diffuse into nuclease

Answer 5

PKA can activate cystolic and nuclear proteins

Question 6

PLC breaks PIP2 down into membrane-associated DAG and cystolic IP3; both of these are signaling molecules and can change function of things

Answer 6

production of IP3 and DAG

Question 7

cell metabolism, cell division, cell movement, cell differentiation, cell survival, cell electrical activity, transcription

Answer 7

signaling pathways can modulate

Question 8

activation of downstream components: extracellular signal molecule>receptor protein>plasma membrane>intracellular signaling proteins>effector proteins (metabolic enzyme>altered metabolism, transcription regulatory protein>altered gene expression, cytoskeletal protein>altered cell shape or movement); signal amplification

Answer 8

basic components of a signal transduction pathway

Question 9

direct cell-cell signaling: both signaling molecules are transmembrane proteins (receptor binding a ligand on the cell); paracrine signaling: nearby, one cell producing some sort of ligand that is acting on cells close by; autocrine signaling: a cell will secrete its own ligand and their receptor would change

Answer 9

short range signaling

Question 10

hormones must diffuse via the blood stream (effects can take years to manifest), uses different hormones to communicate specifically with their target cell, hormones are very dilute in the blood stream and must show great specificity for their receptor, hormones-must be made away from their site of action, be transported, work at physiological concentrations (made by glands)

Answer 10

long range signaling-endocrine signaling

Question 11

can be on the cell surface or intracellular

Answer 11

different receptors

Question 12

nuclear receptors: act as transcription factors to directly alter gene expression, ligand-gated ion channels: respond to neurotransmitters and enable ion flows across membrane, G-protein coupled receptors: respond to signals by activating intracellular trimeric G-proteins that in turn elicit cellular responses, enzyme coupled receptors: respond to a variety of signals and are either enzymes themselves or directly associated with an enzyme

Answer 12

four major classes of signaling receptors

Question 13

direct protein transport through the nuclear pore complex; inactive in the absence of hormone-Glucocorticoids diffuse across the plasma membrane and bind to the glucocorticoid receptor, absence of ligand, the receptor is bound to Hsp90, Glucocorticoid binding causes conformational changes that displace the receptor from Hsp90 and expose nuclear localization signals, allowing nuclear import as receptor dimers, the activated receptors then bind recognition sites in DNA and associate with coactivators with histone acetyltransferase (HAT) activity to stimulate transcription of their target genes; active receptor

Answer 13

nuclear receptors

Question 14

an ion channel that opens in response to the binding of signaling molecules, no permanently open and highly selective

Answer 14

ligand-gated ion channels

Question 15

a receptor characterized by seven membrane-spanning α helices, ligand binding causes a conformational change that activates a G protein; heterotrimeric G proteins, binding of hormone promotes the interaction of the receptor with a heterotrimeric G protein composed of α, β, and γ subunits and with GDP bound to its α subunit, activated receptor acts as GEF and GDP released and GTP bound to alpha subunit which can activate targets, many G-proteins in cells, molecular switches and drug targets

Answer 15

G-coupled protein receptor

Question 16

phospholipids structural and bioactive, sterols (neutral polycyclic membrane lipid), types of sterols present varies by kingdom, sphingolipids-generally bioactive, bioactive molecules temporally regulated and maintained at low levels

Answer 16

lipid components of plasma membrane

Question 17

structural proteins that interact with extracellular matrices (e.g. collagen fiber or cell walls), receptors and signaling complexes, transport proteins (e.g. ion channels, pumps)

Answer 17

protein components of plasma membrane

Question 18

proteins do not remain static, PM is always moving and renewing itself

Answer 18

protein mobility in the membrane

Question 19

refrigerated centrifugation opened the door to enzymatic studies of subcellular compartments, follow with enzymatic assay or western blot, treatment of obtained fractions can help determine membrane associations, molecular bio and confocal microscopy opened the door to many more types of studies

Answer 19

differential centrifugation

Question 20

high salt dissociates peripheral proteins, reducing agent disrupts disulfide linkages, strong detergent removes integral membrane proteins

Answer 20

membrane associations

Question 21

membrane fragments that remain intact with mild detergent treatment, enriched in sterols and signaling machinery/molecules

Answer 21

lipid rafts/detergent resistant microdomains

Question 22

major signaling pathway that will control cell fate, serine/threonine kinase and tyrosine kinase; structural differences, tyrosine is reserved more for receptors and growth changes

Answer 22

phosphorylation of proteins

Question 23

each receptor consists of an N-terminal extracellular ligand-binding domain, a single transmembrane α helix, and a cytosolic C-terminal domain with tyrosine kinase activity, growth factor binding induces receptor dimerization, which results in receptor autophosphorylation as the two polypeptide chains cross-phosphorylate one another

Answer 23

activation of receptor tyrosine kinases

Question 24

proteins with SH2 domains bind to specific phosphotyrosine-containing sites of activated receptors, trans-autophosphorylation: increases kinase activity, creates binding sites for downstream proteins

Answer 24

receptor tyrosine kinases activation and trans-autophophorylation

Question 25

ligand binding induces receptor dimerization and leads to the activation of associated nonreceptor tyrosine kinases as a result of cross-phosphorylation, the activated kinases then phosphorylate tyrosine residues of the receptor, creating phosphotyrosine-binding sites for downstream signaling molecules, function similarly to RTKs

Answer 25

nonreceptor tyrosine kinases

Question 26

growth factor binding to a receptor tyrosine kinase leads to autophosphorylation and formation of binding sites for the SH2 domain of a guanine nucleotide exchange factor (GEF), this interaction recruits the GEF to the plasma membrane, where it can stimulate Ras GDP/GTP exchange, the activated Ras–GTP complex then activates the Raf protein kinase, Raf phosphorylates and activates MEK, a dual-specificity protein kinase that activates ERK by phosphorylation on both threonine and tyrosine residues (Thr-183 and Tyr-185), ERK then phosphorylates a variety of nuclear and cytoplasmic target proteins; cancer related pathway, mutant form of Raf is always active putting the cell in a proliferated state

Answer 26

Ras activates a MAP kinase signaling cascade

Question 27

the interaction of one pathway with another, can be either positive (where one pathway stimulates the other) or negative (where one pathway inhibits the other); different extracellular signal molecule activate different receptors, different receptors have some overlapping targets

Answer 27

signaling crosstalk

Question 28

a regulatory mechanism in which a downstream element of a signaling pathway controls the activity of an upstream component of the pathway; positive or negative feedback (maintains a set point of protein activity and most likely to see with receptor tyrosine kinase)

Answer 28

feedback loops

Question 29

an activated signaling kinase activates a downstream kinase, downstream kinase activates a phosphatase, phosphatase deactivates the kinase

Answer 29

negative feedback

Question 30

an activated signaling kinase activates a downstream kinase, downstream kinase phosphorylates more of the same downstream kinase (so the signal is no longer needed)

Answer 30

positive feedback

Question 31

ATP/AMP (energy currency), glucose (primary carbohydrate of glycolysis), amino acids (protein components/carbon source to make ATP when glucose not present), fatty acids/triacylglycerols

Answer 31

energy status of the cell

Question 32

AMPK (AMP-activated kinase): when active promotes cell program to increase energy available in the cell, mTORC1 (mammalian target of rapamycin complex 1, also a kinase): when active promotes cell program to accommodate plentiful energy

Answer 32

main players in energy signaling axis

Question 33

senses the energy state of the cell and is activated by a high ratio of AMP to ATP, under these conditions, AMPK phosphorylates and activates TSC, leading to inhibition of mTORC1 when cellular energy stores are depleted; functions: upregulation of processes leading to more cellular energy and inhibition processes that take more energy

Answer 33

AMPK

Question 34

couples the control of protein synthesis to the availability of growth factors, nutrients, and energy; complex 2 is one of the protein kinases that phosphorylates and activates Akt, complex 1 is activated downstream of Akt and functions to regulate protein synthesis; raptor and rictor dictate the target specificity of this kinase, raptor (complex 1 dictates what complex is targeting) and rictor (complex 2)

Answer 34

mTOR

Question 35

small G-protein Rheb is the activator of mTORC1, TSC1/2 maintain Rheb in an inactive state via its GAP activity, when TSC1/2 blocked Rheb can remain active and activate mTORC1, many proteins regulate TSC1/2

Answer 35

immediate regulation and function of mTORC1

Question 36

NF-kB and Wnt differentiates from other signaling cascades having a more direct association with plasma membrane signaling to activation of transcription factors

Answer 36

how are these signaling cascades different

Question 37

highly conserved animal pathway involved in the control of cell fate, development, among other processes; genetically discovered in a wingless Drosophila mutant and in a mammalian breast cancer mutation, crosstalk with many other pathways

Answer 37

Wnt signaling

Question 38

unique mechanism, when not active beta-catenin transcription factor constantly turning over, destruction complex promotes phosphorylation and subsequently ubiquitination beta-catenin; when Wnt binds Frizzled receptor LRP, Dishevelled, and Destruction complex form a complex at plasma membrane, destruction complex sequestered from beta-cantenin, beta-cantenin accumulates and translocates to nucleus

Answer 38

Wnt cascade

Question 39

Nf-kB is often referred to as “master regulator of inflammation”, Nf-kB not a single protein but a family of related proteins, downstream signaling molecule of many different receptors including those that are involved in antigen recognition, bacterial pathogenesis and several cytokines, first line signaling defense from stress, chronic inflammation caused by persistent activation of the pathway is associated with disease

Answer 39

NF-kB signaling

Question 40

NF-kB is kept inactive by being bound to the inhibitor IkB, upon receptor activation IkB kinase becomes active and phosphorylates IkB, phospho-IkB is ubiquitinated and degraded, NF-kB is free to translocate to nucleus and activate expression of target genes

Answer 40

NF-kB signaling from the TNF receptor

Question 41

drugs developted that bind to TNF-alpha to treat disease by turning off inflammatory/apoptotic pathways, first one linked part of the receptor to an antibody, subsequent have been antibodies that directly bind TNF-alpha, very effective treatment for many patients

Answer 41

rheumatoid arthritis

Question 42

increased cell division or decreased apoptosis

Answer 42

disrupted balance of normal cell division and apoptosis leads to tumor growth

Question 43

Apoptotic cells and cell fragments are recognized and engulfed by phagocytic cells. One of the signals recognized by phagocytes is phosphatidylserine on the cell surface. In normal cells, phosphatidylserine is restricted to the inner leaflet of the plasma membrane, but it is translocated to the outer leaflet during apoptosis where it is recognized by phosphatidylserine receptors of phagocytic cells; recycling: protecting organism from dangerous cell and reusing its parts

Answer 43

phagocytosis of apoptotic cells

Question 44

cells undergoing this move phosphatidylserine (membrane phospholipid) to outer layer of membrane=eat me signal which can be recognized by its ability to bind the protein annexin that can be fluorescently labeled vs. these dead cells are permeable to propidium iodide, but the other cells are not

Answer 44

distinguishing apoptotic cells vs necrotic cells

Question 45

a member of a family of proteases that bring about programmed cell death; cleave over 100 cellular proteins to induce the morphological alterations characteristic of apoptosis; targets include an inhibitor of DNase (ICAD), nuclear lamins, cytoskeletal proteins, Golgi peripheral membrane proteins, and a scramblase that promotes translocation of phosphatidylserine to the outer leaflet of the plasma membrane

Answer 45

caspases

Question 46

active caspases activate downstream caspases, caspase activation can be extrinsic (extracellular signal) or intrinsic (intracellular damage detected), some crosstalk between

Answer 46

caspase cascade

Question 47

signal to die comes from interaction with killer lymphocyte and to not die comes from extracellular growth factor

Answer 47

caspase activation via extrinsic pathway

Question 48

signal to die comes from within-release of cyt c from mitochondria activates Apaf1, activated Apaf1 assembles into apoptosome, apoptosome recruits and activates caspase-9 thereby triggering caspase cascade

Answer 48

caspase activation via the intrinsic pathway

Question 49

BCL-2 inhibitors interact with members of the BCL2 family of proteins to reduce the production of anti-apoptotic proteins, block the anti-apoptotic defense mechanism of tumor cells, replace and release pro-apoptotic proteins, induce apoptosis, and thus achieve antitumor effects

Answer 49

regulating apoptosis with Bcl2-like proteins

Question 50

apoptotic stimulus triggers activation of BH123 proteins, active BH123 proteins allow for release of mitochondrial contents into cytosol

Answer 50

BH123 proteins

Question 51

when Bcl2 is active it prevents apoptosis, when BH3 proteins are activated, they inactivate Bcl2 thereby promoting apoptosis, expression of BH3 can be activated by p53 in response to DNA damage

Answer 51

inactivation of Bcl2 by BH3

Question 52

TNF and other cell death receptor ligands consist of three polypeptide chains, so their binding to cell death receptors induces receptor trimerization. Caspase-8 is recruited to the receptor and activated by adaptor molecules. Once activated, caspase-8 can directly cleave and activate effector caspases. In addition, caspase-8 cleaves the proapoptotic regulatory protein Bid, which activates the mitochondrial pathway of apoptosis, leading to caspase-9 activation

Answer 52

the extrinsic pathway can recruit the intrinsic pathway

Question 53

increased production of anti-apoptotic Bcl2 family protein, inactivation of pro-apoptotic BH3-only protein

Answer 53

pathways by which apoptosis can be blocked

Question 54

Bcl-2 is anti-apoptotic; Bak, Bax, (BH123) Bid, Bim (BH3) are pro-apoptotic, release of cytochrome C from mitochondria signals apoptosis via Apaf-1, caspases are the proteases that do the work of apoptosis

Answer 54

summary of intrinsic and extrinsic pathways