Signaling Mechanisms Regulating Cell to Cell Communication Flashcards Preview

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Flashcards in Signaling Mechanisms Regulating Cell to Cell Communication Deck (115):
1

Cells can both sense their environment and also influence the behavior/function of other cells by producing secreted

Signaling Proteins

2

This form of communication underlies organ/
tissue physiology and homeostasis in adults,
and is fundamental to

Embryonic Development

3

Include all of the proteins and components that transduce the signal to mediate its effect on the cell

The Signaling Pathway

4

What are the reversible ways that cells respond to signals?

Become motile or change shape

5

What are the irreversible was that cells respond to signals?

Divide, differentiate or remain undifferentiated, and die

6

Allow cells to sense their environment by detecting light, stress or pressure, and chemical signals in the environment

Receptor proteins

7

Which receptor proteins detect light?

Photoreceptors

8

Which receptor proteins detect stress or pressure?

Death receptors (TNFR) and mechanoreceptors

9

A molecule or protein that triggers a signal by binding to a receptor-like protein

Ligand

10

Typically in an inactive state until they receive a signal from the environment

Receptors

11

Once stimulated by ligand binding, receptors do not remain active forever. Some receptors are inactivated by specific mechanisms, while others are inactivated by

Self-inactivation

12

Governed by tertiary (3D) structure and non-covalent bonds between amino acid groups

Specificity of receptor/ligand interaction

13

Any molecule, protein or drug that occupies ligand binding sites and stimulates receptor activity (either
partially or fully)

Agonists

14

Any molecule, protein or drug that occupies ligand binding sites and exclude agonists but does not
stimulate receptor activity

Antagonists

15

Induce receptor activation

Agonists

16

Block receptor activation

Antagonists

17

Underlies cancer, neurological disorders, and metabolic disorders

Abnormal cell-cell signaling

18

About 50% of drugs act on

Receptors

19

The remaining 50% of drugs act primarily on

Enzymes

20

What are the four major classes of receptors?

1.) Ion channels
2.) Steroid hormone receptors
3.) Protein kinase receptors
4.) 7-alpha-helix receptors

21

Pore-forming proteins that allow the flow of ions across
membranes down an electrochemical gradient

Ion channels

22

Ion channels are present only on

Cell surface and intracellular organelles

23

Classified by the nature of their gating, the species of ions passing through, and the number of gates (pores)

Ion channels

24

What are five types of gating seen in ion channels?

1.) ligand
2.) voltage
3.) mechanical or thermal
4.) phospholipid
5.) lipid

25

Binding of ligand opens a channel to allow flow of a
specific ion across the membrane, or closes a channel to stop the flow

Ligand-gated channel

26

Ligand gated channels are the basis for

-i.e. where ligands are neurotransmitters

Nerve transmission & muscle contraction

27

GABA, glycine, serotonin, and nicotinic acetylcholine are examples of

Ligand neurotransmitters

28

Mutations in ion channel genes may cause either a loss or a gain of

Channel function

29

Cystic fibrosis is a recessive disease caused by
loss-of-function mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR)
gene which is a

Chloride channel

30

Mutation in the CFTR gene leads to abnormal salt transport across epithelial cell membranes, resulting in thick mucus build-up in

Respiratory epithelial cells

31

The ligand for CFTR is

ATP

32

Typically associated with dominant inheritance of the disease

Gain-of-function mutations

33

Mutations in voltage-dependent sodium channels can result in defective inactivation and late Na+ currents in

Paramyotonia, cardiac arrhythmia, and epilepsy

34

A sodium channel blocker that blocks action potentials in nerves

-Found in pufferfish or Fugu

Tetrodoxin

35

Proteins that function by controlling gene expression

-hydrophobic and can cross the cell membrane
-derived from cholesterol

Steroid hormones

36

Steroid hormones bind to receptors located in the

Cytosol or nucleus

37

For estrogen, prior to ligand binding, the steroid hormone receptor is attached to a

Chaperone protein

38

Induces a conformational change in the
receptor that causes dissociation from the chaperone protein and exposes a nuclear import signal, allowing homodimerization and subsequent nuclear entry

Estrogen binding

39

Dimerized receptors bind to an estrogen response element (ERE, a DNA promoter) that activates

Activates gene transcription

40

Overexpressed in cancer cells in 70% of breast cancer cases

Estrogen receptors

41

Estrogen sensitive (ER+) breast cancer cells require signaling for uncontrolled cell division and

DNA replication

42

Involves the use of selective estrogen receptor (i.e., competitive) antagonists, such as tamoxifen

Endocrine therapy

43

In breast tissue, tamoxifen is metabolized into a
protein, hydroxytamoxifen (H-tam) that binds to the
ER and prevents binding of

Estrogen

44

Functions to repress rather than activate estrogen target genes via recruitment of transcriptional co-repressors

ER/H-tam complexes

45

A protein or protein domain with enzymatic
activity that transfers phosphate groups from
high energy donor molecules such as ATP to
specific target molecules.

Kinase

46

Are composed of three domains:
1. An extracellular domain that binds the ligand
2. A trans-membrane domain
3. A cytoplasmic domain that has kinase activity or binds a protein-kinase protein

Protein kinase receptors

47

Active kinase receptors are typically

Dimers (or other forms of oligomer)

48

What are the two major subfamilies of protein kinase receptors?

-defined by the amino acid phosphorylated

1.) Tyrosine kinases
2.) Serine/threonine kinases

49

One of the most well known receptor tyrosine kinases is the

Insulin receptor

50

Describe how the receptor kinase works?

1.) Ligand binds to extracellular domain of each receptor subunit causing dimerzation
2.) The cytosolic protein kinase domains phosphorylate and activate each other (often at multiple positions)
3.) Aditional cytosolic proteins are recruited to and bind the phosphorylated receptors

51

A reversible process that can regulate whether a receptor is "on" or "off"

Phorphorylation

52

The addition of a phosphate molecule to a polar R
group of an amino acid (like tyrosine) can turn a
hydrophobic portion of a protein into a

Hydrophilic one

53

This can give rise to a conformational change which can facilitate interaction with other parts of the protein or with other

Molecules

54

Contains an SH2-domain that recognizes tyr-P and binds to phosphorylated receptors

Grb

55

Binds to Grb and activates small G-proteins such as Ras

SoS (a GEF)

56

SoS binds to Grb and activates small G-proteins such as the prototypic monomeric small G-protein

Ras

57

Activate G-proteins by catalyzing the exchange of GDP (inactive) for GTP (active)

Guanine Nucleotide Exchange Factors (GEFs)

58

Promote inactivation of G-proteins by stimulating conversion of GTP (active) to GDP (inactive) via hydrolysis

GTPase activating proteins (GAPs)

59

Bind guanine nucleotides and act as a molecular switch during signaling

G-proteins

60

Have intrinsic GTPase activity

G-proteins

61

The GTPase activity of G-proteins is stimulated by

GAPs

62

The replacement of GDP by GTP is stimulated by

GEFs

63

Receptor bound SoS is

ras-GEF (ras-guanine exchange factor)

64

Regulate many aspects of cell function

Small G-proteins

65

The Ras protein family is actually a small family of proteins made up of

H-, K-, and N-Ras

66

Functions in receptor signaling and cell division

Ras family

67

Functions in traffic of membrane vesicles

Rab family

68

Functions in nucleus/cytoplasmic traffic

Ran family

69

Functions in the actin cytoskeleton

Rac family

70

Proteins like the Mitogen Activated Protein Kinae (MAPK) with ras-GTP cause a phosphorylation cascade that activates

-stimulates production of proteins involved in cell division

Transcription factors

71

Serves as a convergence point for many signals

Ras

72

Ras is one of the most frequently altered proteins in

Human Tumors

73

Oncogenic mutations in Ras turn all of its down stream pathways

On

74

Most oncogenic mutations of Ras are amino acid substitutions at just two positions. What are the two positions?

gly-12/gly-13 or gln-61

75

These mutations affect the structure of Ras and abolish its ability to hydrolyze GTP, so it is always in the

Active state

76

What are two ofther Ras-related disease?

Neurofibromatosis Type-1 and Noonan Syndrome

77

Caused by a mutation in the NF1 gene, which results in overactive Ras. This gene encodes neurofibromin-1, a Ras-GAP.

Neurofibromatosis type 1

78

Caused by a mutation in the PTPN11 gene which encodes SHP2. This results in a gain of function phenotype which leads to hyperactive Ras

Noonan Syndrome

79

The most abundant class of receptors

7-α-helix receptors

80

Most receptor targeted drugs are directed at

7-α-helix receptors

81

What are four physiological roles for 7-α-helix receptors?

Vision, smell, mood, and autonomic nervous system

82

Opsins (7-α-helix receptors), such as rhodopsin, convert electromagnetic radiation (light) into

Cellular signals

83

7-α-helix receptors for neurotransmitters bind serotonin, dopamine, GABA, and glutamate to affect

Mood

84

Both sympathetic and parasympathetic nervous systems are regulated by G-Protein-coupled

7-α-helix receptors

85

7-α-helix receptors are coupled to trimeric "large G-proteins" whose α-subunits contain

Ras-like domains

86

Ligand binding to 7-α-helix receptors causes exchange of GDP by GTP and activation of the G-protein, initiating

Signaling Cascade

87

The 7-α-helix receptor itself thus acts as a

GEF

88

Dissociate from ligand-bound receptors and regulate activity of downstream proteins

α and βγ subunits

89

What are the three main subclasses of large G-proteins α-subunits?

Gs-α, Gi-α, and Gq-α

90

Activates adenylate cyclase which activates protein kinase A (PKA)

Gs-α

91

Inhibits adenylate cyclase, which inhibits protein kinase A (PKA)

Gi-α

92

Activates phospholipase-Cβ (PLC) which affects Protein kinase C (PKC)

Gq-α

93

Desensitization/dialing back the response, is when the receptor signaling diminishes or terminates, even in the presence of

Ligand

94

7-α-helix receptor that binds the adrenal-gland hormone epinephrine and the neurotransmitter norepinephrine.

β-adrenergic receptor

95

The ligand-bound β-adrenergic receptor becomes substrate for

β-adrenergic receptor kinase (BARK)

96

The phosphorylated β-adrenergic receptor is bound by

-blocks interaction with Gs

β-arrestin

97

Ligand-bound β-adrenergic receptor is inactivated by a
protein kinase and

-terminates signaling even in the presence of the ligand (desensitization)

β-arrestin

98

Cytosolic calcium is maintained at a very low
concentration by calcium pumps in the plasma
membrane and the

Smooth ER (SER)

99

Triggers many events in cells such as muscle contraction, regulated secretion, and cell division

Receptor-mediated calcium influx

100

Gi-α inhibits adenylyl cyclase, which then prevents PKA from becoming active. This prevents

Calcium influx

101

Gs-α activates adenylyl cyclase, which in turn activates PKA, which allows for

Calcium influx

102

Gq-α-GTP activates phospholipase-C (PLC) and triggers

Ca2+ release from the Smooth ER (SER)

103

Gq-α-GTP activates phospholipase C (PLC), which hydrolyzes membrane phosphatidyl inositol-
4,5-diphosphate (PiP2) into

iP3 and diacyl glycerol (DAG)

104

Triggers release of Ca2+ from lumen of SER into cytoplasm

iP3

105

DAG and Ca2+ then activate

Protein kinase C (PKC)

106

Most kinases are inactive because they are

inhibited

107

Frees kinases from inhibition

Receptor activation

108

Inactive because its active site is filled with an N-terminal pseudosubstrate peptide, held in place by its
C1 and C2 domains

PKC

109

Bind DAG in membranes

C1 domains

110

In the presence of Ca2+ the C2 domain binds

-found in the inner leaflet of the plasma membrane

Phosphatidyl Serine (PS)

111

This removes the pseudosubstrate from the active site and PKC becomes active. It can then be cleaved proteolytically and PKC is then

Constitutively (permanently) active

112

A calcium-binding protein that regulates the activity of many proteins

-binds 4 Ca2+ ions

Calmodulin

113

Is closely related to the calcium-binding subunit
of the protein troponin which regulates muscle
contraction

Calmodulin

114

Ca2+ bound calmodulin activates many proteins,
including another self-inhibited kinase known as

Calmodulin-activated protein kinase (CAMK)

115

An important mediator of learning and
memory and has been implicated in AD

-others are involved in cancer and musculoskeletal diseases

CAMKII

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