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Flashcards in Cell Signaling Deck (24)
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1
Q

Specificity of receptor-ligand interactions is governed by _____ structure and _______ bonds between _____.

A

Specificity of receptor-ligand interactions is governed by TERTIARY structure and NON-COVALENT bonds between AMINO ACIDS.

2
Q
Ion channels are important for:
Transport of \_\_\_\_ and \_\_\_\_\_
Chemical signaling (\_\_\_ channels)
Regulation of cellular \_\_\_\_\_ and \_\_\_\_\_
\_\_\_\_\_ of intracellular organelles
A
Ion channels are important for:
Transport of SALT and WATER
Chemical signaling (Ca2+ channels)
Regulation of cellular VOLUME and pH
ACIDIFICATION of intracellular organelles
3
Q

The ligand for CFTR is ____
Mutation in CFTR results in abnormal ____ transport across _____ cell membranes, resulting in ________ in respiratory _____ cells.

A

The ligand for CFTR is ATP
Mutation in CFTR results in abnormal SALT transport across EPITHELIAL cell membranes, resulting in THICK MUCUS BUILD-UP in respiratory EPITHELIAL cells.

4
Q

Gain of function mutations in ion channels are typically associated with _____ inheritance of the disease. Usually results in ______ activation.

Mutations in Na+ channels can result in _______ and _______ in _____, _____ and ____.

A

Gain of function mutations in ion channels are typically associated with DOMINANT inheritance of the disease. Usually results in CONSTITUTIVE activation.

Mutations in Na+ channels can result in DEFECTIVE INACTIVATION and LATE Na+ CURRENTS in PARAMYOTONIA, CARDIAC ARRHYTHMIA and EPILEPSY.

5
Q

Tetrodotoxin is a _____ channel blocker

A

Tetrodotoxin is a SODIUM channel blocker

6
Q

Nuclear steroid hormone receptor mech of action:
Receptor is usually found in _____. When ligand is not bound, receptor usually binds to ______. The ligand can displace the ______, exposing an ___ so the lignad-receptor complex can enter and act as transcription factors by binding to ____. These receptors _____ either before or entering nucleus, and this is necessary for acticvation (if _________ is a part of the specific pathway)

A

Receptor is usually found in CYTOPLASM (CAN ALSO BE FOUND IN NUCLEUS). When ligand is not bound, receptor usually binds to CHAPERONE. The ligand can displace the CHAPERONE, exposing an NLS so the lignad-receptor complex can enter and act as transcription factors by binding to HREs. These receptors DIMERIZE either before or entering nucleus, and this is necessary for acticvation (if DIMERIZATION is a part of the specific pathway)

This example was specific for estrogen

7
Q

Treatment of estrogen-sensitive breast cancer:
ER+ breast cancer cells require _____ for cell division and DNA replication.

Endocrine therapy involves the use of ER ______ such as _____.
In breast tissue, _____ is metabolized into a protein, ________ that binds to the E-receptor and prevents __________.

ER/_____ complex functions to _______ estrogen target genes via _____________.

A

Treatment of estrogen-sensitive breast cancer:
ER+ breast cancer cells require SIGNALING for cell division and DNA replication.

Endocrine therapy involves the use of ER ANTAGONISTS such as TAMOXIFEN.
In breast tissue, TAMOXIFEN is metabolized into a protein, H-TAM that binds to the E-receptor and prevents BINDING OF ESTROGEN.

ER/H-TAM complex functions to REPRESS estrogen target genes via RECRUITMENT OF TRANSCRIPTIONAL CO-REPRESSORS.

8
Q

Protein kinase receptors either have a ______domain or _______________.

They are made up of: _____ domain that binds ligand, ______ domain, and the domain mentioned above.

Active receptors contain typically _ or more polypeptide chains (they must _____ for activation).

Ligand binding induces ______ which leads to ____. Cascade of _____ occurs after ______.

Two major subfamilies:
_____ kinases —> insulin, EFG, FGF, PDGF, VEGF, Trk

_____ kinases —> cytokines, TGF-B

A

Protein kinase receptors either have a INTRACELLULAR PK domain or BINDS A PK PROTEIN.

They are made up of: EXTRACELLULAR domain that binds ligand, TRANS-MEMBRANE domain, and the domain mentioned above.

Active receptors contain typically TWO or more polypeptide chains (they must DIMERIZE for activation).

Ligand binding induces CONFORMATIONAL CHANGE which leads to DIMERIZATION. Cascade of PHOSPHORYLATION occurs after DIMERIZATION.

Two major subfamilies:
TYROSINE kinases —> insulin, EFG, FGF, PDGF, VEGF, Trk

SERINE/THREONINE kinases —> cytokines, TGF-B

9
Q

Mechanism of PK Receptor Activation
Ligand binds extracellular domain of ____ receptor subunit.

Subunits _____, binding _____ _____ domains closer together.

_____ ______ and activate each other.

Activated ____ are often ______ at multiple positions.

Additional ______ proteins bind ______ receptors (via _____).

A

Mechanism of PK Receptor Activation
Ligand binds extracellular domain of EACH receptor subunit.

Subunits DIMERIZE, bringing CYTOSOLIC PK domains closer together.

KINASES PHOSPHORYLATE and activate each other.

Activated KINASES are often PHOSPHORYLATED at multiple positions.

Additional CYTOSOLIC proteins bind PHOSPHORYLATED receptors (via RECRUITMENT).

10
Q

Grb protein ________ due to ________ in RTKs. It binds ______ via it’s ____ domain which recognizes ____.

A

Grb protein RECOGNIZES CONFORMATIONAL CHANGE due to PHOSPHORYLATION in RTKs. It binds PHOSPHORYLATED RECEPTORS via it’s SH2 domain which recognizes TYR-P.

11
Q

SoS protein is a _____ protein involved in the ____ pathway, and it binds to ______ in order to activate ________ such as ____.

A

SoS protein is a GEF protein involved in the RAS pathway, and it binds to GRB in order to activate SMALL G-PROTEINS such as RAS.

12
Q

GEFS _____ g-proteins by catalyzing _____ of GDP for GTP.

GAPS promote _____ of g-proteins by _______ ______ of GTP to GDP via ________.

G-proteins bind ____ _____ and act as a molecular switch during signaling. They have intrinsic _____ activity.

A

GEFS ACTIVATE g-proteins by catalyzing EXCHANGE of GDP for GTP.

GAPS promote INACTIVATION of g-proteins by STIMULATING CONVERSION of GTP to GDP via HYDROLYSIS.

G-proteins bind GUANINE NUCLEOTIDES and act as a molecular switch during signaling. They have intrinsic GTPase activity.

13
Q

Small G-proteins that regulate many aspects of cell function:

Ras: _____ signaling and ____ _______
Rab: _____________
Ran: __________
Rac: ____ cytoskeleton

A

Small G-proteins that regulate many aspects of cell function:

Ras: RECEPTOR signaling and CELL DIVISION
Rab: TRAFFIC OF MEMBRANE VESICLES
Ran: NUCLEUS/CYTOPLASM TRAFFIC
Rac: ACTIN cytoskeleton

14
Q

Ras-MAPK Pathway after binding receptor complex:

MAPK ______ activates _____ ______, which stimulate production of proteins involved in _____ ______.

A

Ras-MAPK Pathway after binding receptor complex:

MAPK CASCADE activates TRANSCRIPTION FACTORS, which stimulate production of proteins involved in CELL DIVISION.

15
Q
Ras is activated by multiple \_\_\_\_\_\_\_\_\_\_\_.
Downstream effectors of ras:
\_\_\_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_
\_\_\_\_ \_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_ \_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_

Oncogenic mutations in ras turn all of it’s downstream pathways ___.

Most oncogenic mutations are AA substitution at ______ or _____, which affect the _______ of ras and __________ it’s ability to ________, so it’s always in ______ state.

A
Ras is activated by multiple LIGAND/RECEPTOR TYPES.
Downstream effectors of ras:
CELL GROWTH AND DIVISION
CYTOSKELETON
CELL ADHESION
MEMBRANE TRAFFIC
ANTI-APOPTOSIS

Oncogenic mutations in ras turn all of it’s downstream pathways ON.

Most oncogenic mutations are AA substitution at GLY-12/13 or GLN-61, which affect the STRUCTURE of ras and ABOLISH it’s ability to HYDROLYZE GTP–>GDP, so it’s always in ACTIVE state.

16
Q

Neurofibromatosis type-1 is caused by mutation in the ___ gene, which encodes ______, a ______. This results in overactive _____.

A

Neurofibromatosis type-1 is caused by mutation in the NF1 gene, which encodes NEUROFIBROMIN-1, a RAS-GAP. This results in overactive RAS.

17
Q

Noonan Syndrome is caused by a mutation in the _____ gene which encodes _____ (docking protein). This results in a _______ phenotype which leads to hyperactive ______.

A

Noonan Syndrome is caused by a mutation in the PTPN11 gene which encodes SHP2 (docking protein). This results in a GAIN-OF-FUNCTION phenotype which leads to hyperactive RAS.

18
Q

7-alpha helix receptors contribute to our _____. Examples are _____, ______, _____ receptors, and ________.

They are coupled to ______ large G-proteins whose _ subunits contain ___-like domains

Ligand binding causes _______ and activation of the G-protein, where _ dissociates from ___, initiating __________.

The receptor acts as a _____.

A

7-alpha helix receptors contribute to our SENSES. Examples are RHODOPSIN, OLFACTORY RECEPTORS, MOOD receptors, and SYMPATHETIC AND PARASYMPATHETIC G-PCRS.

They are coupled to TRIMERIC’ large G-proteins whose A subunits contain RAS-like domains

Ligand binding causes EXCHANGE OF GDP FOR GTP and activation of the G-protein, where A dissociates from B-G, initiating SIGNALING CASCADE.

The receptor acts as a GEF.

19
Q

Three main subclasses of G-protein alpha subunits

Gs Alpha: _____ adenylate cyclase (downstream effector is ___)
Gi Alpha: _____ adenylate cyclase (downstream effector is ___)
Gq Alpha: activates ________ (downstream effector is ____)

A

Three main subclasses of G-protein alpha subunits

Gs Alpha: ACTIVATES adenylate cyclase (downstream effector is PKA)
Gi Alpha: INHIBITS adenylate cyclase (downstream effector is PKA)
Gq Alpha: activates PLC (downstream effector is PKC)

20
Q

Desensitization of G-Protein Coupled Receptor
-when receptor signaling _____ even in presence of ______

Example: ___________ receptor, which binds the hormone _____ and the NT ______

Ligand-bound receptor becomes substrate for _______, which is a _____.

______-ted receptor is bound by _______, which blocks interaction with Gs subunit

A

Desensitization of G-Protein Coupled Receptor
-when receptor signaling DIMINISHES even in presence of LIGAND

Example: B-ADRENERGIC RECEPTOR receptor, which binds the hormone EPI and the NT NOREPI

Ligand-bound receptor becomes substrate for BARK, which is a KINASE.

PHOSPHORYLAted receptor is bound by B-ARRESTIN, which blocks interaction with Gs subunit

21
Q

Adenylate Cyclase Pathway:
Ligand binds receptor, _____ dissociates from ______, causing activation of adenylate cyclase, which causes formation of _____, which activates ______, which leads to release of ____ ions.

Usually, these ions are maintained at a ____ [] by ____ in the _____ and ____. Receptor-mediated ___ influx triggers _____, ______, and ____.

___ And ___ stimulate release of these ions, whereas ____ and ____ activate the inhibitory subunit, which goes against the previous action. Both mechanisms can act at the same time to regulate previously mentioned cellular functions.

A

Adenylate Cyclase Pathway:
Ligand binds receptor, GS-ALPHA dissociates from BETA AND GAMMA, causing activation of adenylate cyclase, which causes formation of C-AMP, which activates PKA, which leads to release of CALCIUM ions.

Usually, these ions are maintained at a LOW [] by PUMPS in the PM and SER. Receptor-mediated CA++ influx triggers MUSCLE CONTRACTION, REGULATED SECRETION, and CELL DIVISION.

EPI And NOREPI stimulate release of these ions, whereas ACH and ADENOSINE activate the inhibitory subunit, which goes against the previous action. Both mechanisms can act at the same time to regulate previously mentioned cellular functions.

22
Q

Gq proteins in G-pcrs activate ______ and triggers ____ release from ____.

____ hydrolyzes membrane ________ into _____ and ____.

____ triggers release of ____ from lumen of _____ into ____.

____ and ____ activate PKC.

A

Gq proteins in G-pcrs activate PLC and triggers CA++ release from SER.

PLC hydrolyzes membrane PIP2 into IP3 and DAG.

IP3 triggers release of CA++ from lumen of SER into CYTOPLASM.

DAG and CA++ activate PKC.

23
Q

Mechanism of PKC activation:

Full binding of PKC’s __ domain to _____ requires the presence of ___ ions for the __ domain to bind __ in the inner leaflet of PM.

PKC is normally inactive because __ domain’s ____ structure (in the form of a N-terminal _______) blocks catalytic site.

When there is ____ signaling, ____ is produced from the cleavage of ____ in the membrane, and ____ + ____ become substrates for __ and __ domains (respectively). This causes conformational change, leading to ___ of ____ domain so it can do work in cytoplasm.

A

Mechanism of PKC activation:

Full binding of PKC’s C2 DOMAIN to PS requires the presence of CA++ ions for the domain to bind PS in the inner leaflet of PM.

PKC is normally inactive because C1 domain’s TERTIARY structure (in the form of a N-terminal PSEUDOSUBSTRATE) blocks catalytic site.

When there is PLC signaling, DAG is produced from the cleavage of PIP2 in the membrane, and DAG + PS become substrates for C1 and C2 domains (respectively). This causes conformational change, leading to CLEAVAGE of KINASE domain so it can do work in cytoplasm.

24
Q

Calmodulin requires binding of _ Ca2+ ions. It activates a self-inhibited kinase called ____.

____ normally has it’s active site blocked by a _____. Active calmodulin binds this ____ to make the active site accessible.

____ is an important mediator of learning and memory and has been implicated in __.

Other ____ proteins are involved in ____ and ____.

A

Calmodulin requires binding of FOUR Ca2+ ions. It activates a self-inhibited kinase called CAMK.

CAMK normally has it’s active site blocked by a INHIBITORY DOMAIN. Active calmodulin binds this INHIBITORY DOMAIN to make the active site accessible.

CAMKII is an important mediator of learning and memory and has been implicated in AD.

Other CAMK proteins are involved in CANCER and MUSCULOSKELETAL DISEASES.