cell signaling Flashcards
(58 cards)
1
Q
what is signal transduction?
A
process where cells communicate with the external and internal environment, with neighboring cells, and with oneself
2
Q
why do cells need to communicate with each other?
A
to live in a harmonious way by coordinating actions with each other
3
Q
what can defects in cell signaling result in?
A
diseases such as insulin signaling defect which causes diabetes mellitus
4
Q
what are the basic components of a signaling pathway?
A
- signal molecule or ligand (can be extracellular or intracellular)
- receptor protein on the plasma membrane or in the cytoplasm
- intracellular signaling proteins
- effector proteins
5
Q
define endocrine signaling
A
- extracellular
- happens at a great distance
- examples include hormone secretion and insulin
- falls in secreted ligands category
6
Q
define paracrine signaling
A
- extracellular
- ligands secreted into extracellular space and travel between adjacent cells
7
Q
define autocrine signaling
A
- extracellular
- self signaling occurring on the same cell
- example would be growth factor secretion that stimulates the proliferation of the same cell
8
Q
define plasma-membrane-attached protein signaling
A
- is a type of extracellular signaling
- can be classified as paracrine (between adjacent cells)
9
Q
what is the Notch Delta pathway?
A
- example of paracrine signaling
- occurs between adjacent cells
- delta is the ligand and notch is the receptor
- as delta binds to notch, notch is cleaved and the tail migrates to the nucleus to induce gene transcription
10
Q
what are the two types of receptors?
A
- cell surface or intracellular receptors
- cell surface bind to surface of cell and usually have a hydrophilic signal molecule that cannot cross the membrane
- intracellular receptors are present in the cytoplasm or nucleus
- intracellular receptors have hydrophobic signal molecule that can cross the plasma membrane
11
Q
_______ can be in the cytoplasm and once bound can undergo a conformational change to move to the nucleus
A
intracellular receptors
12
Q
what is an example of an intracellular signal molecule (ligand)?
A
steroid and thyroid hormones
13
Q
describe the basic steroid hormone pathway
A
hormone passes through membrane and binds with receptor protein inducing a conformational change that activates the receptor protein. activated receptor-hormone complex moves into the nucleus where it binds to the regulatory region of the target gene to activate transcription.
14
Q
what is the minimal pathway?
A
- signaling pathway composed of a signal molecule and a receptor-effector protein
- the receptor functions as its own effector
- examples include the steroid hormone pathway and the notch-delta pathway
15
Q
describe the three types of effector proteins and their effect
A
- metabolic enzyme: can lead to altered metabolism
- gene regulatory protein: can lead to altered gene expression
- cytoskeletal protein: can lead to altered cell shape or movement (migration)
16
Q
what would result in a FAST response rate?
A
change in protein function (example: protein phosphorylation)
17
Q
what would result in a SLOW response rate?
A
producing new proteins (example: gene transcription)
18
Q
what is the primary function of the signal transduction pathway?
A
to relay the signal to the cell
19
Q
what are some additional functions of the ST pathway?
A
- to transduce and amplify signal
- to integrate signals from various signaling pathways
- to distribute the signal to more than one effector protein
20
Q
describe signal amplification and the benefit involved in this function
A
- signal amplification involves the relaying of a signal from 1 molecule to 100 molecules to 10,000 molecules (a cascade)
- the more components you have the more control you can have over the pathway
21
Q
describe what switch proteins are
A
- proteins that can switch between active and inactive form
- function as signaling proteins
- usually involve a cascade that turns effector on and leads to cellular response
- classified as either phosphorylated proteins or GTP-binding proteins
22
Q
describe second messengers
A
- NOT proteins but small molecules that aid in signaling
- examples include calcium or lipid molecules
- activated by the activation of an enzyme which releases the second messenger
23
Q
how are phosphorylated proteins regulated between active and inactive state?
A
- addition of phosphate due to kinase switches protein from inactive to active
- removal of phosphate due to phosphatase switches protein from active to inactive
24
Q
what amino acids are useful in kinase activity (protein phosphorylation)
A
serine, threonine and tyrosine due to the hydroxyl group on side chain
25
GTP-binding proteins are an example of __________ regulation
non covalent
26
what are the two types of GTP-binding proteins?
monomeric GTPases and trimeric GTP-binding proteins (aka G proteins)
27
how are GTP-binding proteins regulated between active and inactive state?
- GTP binding (removal of GDP) switches from inactive to active
- GDP binding (removal of GTP) switches from active to inactive
28
describe the role of GAP and GEF in the activity cycle of GTP-binding proteins
- GAP allows for faster exchange of GTP to GDP (faster switch from active to inactive state)
- GEF exchanges GDP with GTP for faster activation
29
how can mutations in GEF and GAP influence the activity cycle?
- a mutation in GAP can cause GTP to be bound all the time so the protein is always active
- a mutation in GEF means the protein is always inactive
30
trimeric GTP-binding proteins use __________ instead of GEF
GPCR
31
what is Ras?
- it is a monomeric GTPase
- exists as a single protein
- activated by receptor tyrosine kinase
- mutant form can cause permanent GTP bound conformation leading to proliferation and cancer
32
Ras is especially activated in pathways that stimulate _____________ and ____________
cell division, cell differentiation
33
what is the first messenger in ST pathway?
the signal molecule (ligand)
34
what is the purpose of second messengers?
they diffuse to act on intracellular signaling proteins after activation by an enzyme
35
what are some examples of second messengers?
- cAMP
- calcium
- cGMP
- diacylglycerol
- IP3
- PIP3
36
______ is a cAMP phosphodiesterase inhibitor
caffeine
37
______ is a cGMP phosphodiesterase inhibitor
viagra (sildenafil citrate)
38
describe the pathway involving IP3 and DAG
- PLC is activated
- causes the release of IP3 and DAG through cleavage of phospholipid into two
- DAG activates protein kinase C
- addition of phosphate to PIP2 forms PIP3
- IP3 prompts release of calcium from ER
- calcium results in conformational change of calmodulin
- calmodulin activation prompts signal response
39
how can signal transduction be terminated?
- receptor down regulation which takes away the ligand
- second messenger can be degraded
- phosphatases can remove P to turn it off
- negative feedback regulation can turn off production
40
what are g protein coupled receptors (GPCRs)?
- largest family of cell-surface receptors
- they mediate responses to a wide variety of signal molecules
- examples: hormones, neurotransmitters, small peptides, amino acid derivatives and fatty acid derivatives
41
describe the structure of GPCRs
they are coupled to a heterotrimeric (alpha, beta, and gamma) G protein and span the plasma membrane 7 times. the alpha unit is the GTP binding protein.
42
describe the process of activation in skeletal muscle cells
- GPCR is activated
- alpha subunit acts as switch protein changing ATP to cAMP
- cAMP activates PKA by inducing a catalytic change (4 cAMP molecules needed)
- active PKA induces phosphorylation of active phosphorylase kinase
- active phosphorylase kinase activates glycogen phosphorylase which leads to glycogen breakdown
43
what is the difference between Gs and Gi?
- Gs is a stimulatory protein that once activated separates from the beta and gamma subunits to stimulate enzyme activity
- Gi is an inhibitory protein that binds to the enzyme and inhibits enzyme activity
44
what is the end goal of liver cell activation?
active PKA leads to phosphorylation of glycogen phosphorylase and phosphorylase kinase
45
what is the end goal of fat cell activation?
active PKA leads to phosphorylation of phospholipase which results in breakdown of phospholipids
46
describe receptor associated tyrosine kinase signaling
- cytokine ligand binds
- binding induces dimerization of receptors which are bound to JAK (kinase)
- dimerization converts inactive JAK to active JAK (phosphorylation)
- active JAK phosphorylates STAT
- phosphorylated STAT dimerizes and moves to nucleus to activate transcription
47
what is the importance of an SH2 domain in receptor associated tyrosine kinase signaling?
the SH2 domain helps bind to phosphotyrosine residues and induces a conformational change to allow for phosphorylation by JAK and dimerization
48
describe the two mechanisms for terminating cytokine signal transduction
- short-term: JAK2 deactivation by SHP1 phosphatase causing dephosphorylation (of JAK2 moving to inactive state)
- long-term: signal blocking and protein degradation by SOCS proteins that recruit E3 ubiquitin ligase which induces degradation of JAK2 and receptor
49
describe RTK activation
- ligand (ex: EGFR, FGF) binds to ligand binding site
- binding causes dimerization and activation of protein tyrosine kinase
- cross-phosphorylation of additional tyrosine residues
- GRB2 binds to RTK complex (GRB2 has a SH2 domain)
- GRB2 recruits Sos protein which then activates Ras to transmit signal
50
define the Ras activation pathway
- activated RTK binds to adaptor protein (GRB2)
- GRB2 recruits and binds to Ras-GEF (Sos protein)
- Sos activates Ras by switching GDP to GTP
- activated Ras activates MAP3K
- MAP3K phosphorylates and activates MAP2K
- MAP2K phosphorylates and activates MAPK
- MAPK then goes on to activate other proteins to result in transcriptional induction
51
explain the difference between MAPK direct and indirect phosphorylation
MAPK can directly phosphorylate TCF to result in transcription or it can activate p90rsk that can then phosphorylate SRF which activates TCF and leads to transcription
52
describe TGFbeta signaling
- ligand (TGFbeta) can bind to receptor III then transfer to receptor II or ligand can bind directly to receptor II
- once bound to receptor II, receptor I is bound inducing serine-threonine kinase activity
- receptor complex phosphorylates Smad3
- Smad activation causes Smad3 and Smad4 to dimerize
- dimerization leads to transcription activation
53
explain hedgehog signaling
- ligand (hedgehod) binds to Ptc receptor
- binding induces movement of Smo to plasma membrane
- movement of Smo dissociates the protein complex holding Ci (SUFU still bound to protect Ci)
- Ci is free to move into nucleus and induce transcription
54
what happens under (-) Hh signaling?
- hedgehog is not bound to Ptc receptor
- this actively induces endocytosis of Smo
- protein complex holding Ci remains intact
- Ci75 moves into nucleus and inhibits transcription
55
explain (+) Wnt signaling
- Wnt ligand binds to receptor Frizzled and LRP co-receptor
- binding triggers GSK3 and CK1 to phosphorylate LRP
- axin binds to phosphorylated LRP causes disruption of complex holding beta-catenin
- free beta-catenin can move into nucleus and induce transcription
56
what occurs in the absence of Wnt?
- beta-catenin is bound in complex and headed for proteasomal degradation
- Groucho binds to TCF in nucleus and inhibits transcription
57
hyperactive _____ signaling can lead to the progression of cancers, in particular human ______ cancer
Wnt, colon
58
explain Notch signaling
- Notch binds to Delta on an adjacent cell
- Delta and release Notch extracellular domain are endocytosed together by signaling cell
- nicastrin subunit binds to Notch stump left on responding cell
- presenilin 1 protease catalyzes cleavage to release the Notch stump
- Notch stump moves to nucleus to activate transcription factors
