Cell Signaling Flashcards
_____ molecules work in combinations to regulate the behavior of the cell. Cells require signals to ____ and ____. _____, or programmed cell death will occur if a cell does not receive appropriate signals
Signal
Survive
Divide
Apoptosis
____ ____ (_____): signaling requiring physical contact between cells.
_____: cells signaling to themselves
____: cells signaling to neighbor cells
_____: signaling to distant cells usually via secreted hormones
Contact dependent (Juxtacrine)
Autocrine
Paracrine
Endocrine
A ____ is a signaling molecule produced by one cell that binds to a receptor on either the same or another cell
Ligand
A _____ becomes activated by a Ligand resulting in receptor driven changes in Intracellular protein-protein interactions and/or enzyme activity. This is referred to as ____ ___
Receptor
Signal transductions
Signal transduction results in the activation or release of other small Intracellular molecules called ____ ___. Ex: cAMP, cGMP, IP3, DAG, Ca++
Second messengers
If a signaling molecule is hydrophilic it will most likely bind to _____ receptors. If a signal molecule is hydrophobic it will most likely bind to ____ receptors.
Extracellular
Intracellular
Hydrophobic signal molecules can ____ across the plasma membrane to bind to receptors inside the cell, usually in the ____ or ____.
Such signals are generally transported into the blood stream and other extracellular fluid via _____ proteins and then dissociate before entering the target cell.
Diffuse
Cytoplasm
Nucleus
Carrier
Different cells respond differently to the ___ signal molecule due to different receptors, different signal transduction, different second messenger. An example of this is _____, it decreases contraction of cardiomyocytes but stimulates contraction in skeletal muscle
Same
Acetylcholine
____ ____ loops occur if an upstream molecule regulates a downstream target through two or more separate mechanisms or pathways
Feed forward
___ ___ loops amplify a response through the ability of a product to increase the activity of an earlier component of the pathway
Positive feedback
____ ___ loops limit a response by the ability of a product to inhibit the activity of an earlier component of the pathway
Negative feedback
____ ____ vary in strength with the signal molecule concentration. These types are particularly evident during ___ ___, when the organization of the body plan is being determine. Example: ____ in low levels promotes blood cell differentiation, whereas in high levels it promotes muscle differentiation
Graded response
Early development
Activin
______ ____ are signals that turn on and off which suddenly and rapidly change cell behavior. Example: the decisions in cell division and regulated cell death
Switch-like responses
What mechanisms determine weather the response is graded or switch like?
The concentration of a molecule can be adjusted rapidly only if it’s half life is ____
Short
The response increases with an ____ in the number of effector molecules that must bind simultaneously to activate a target
Increase
Switch like functions in a cell signaling pathway can involve _____ or ____.
Phosphorylation
G proteins
G proteins are activated by ___ and inactivated by ____. Two major categories include ____ G proteins which relay signals from G protein linked receptors. _____ G proteins regulate multiple Intracellular events
GTP
GDP
Trimeric
Monomeric
Many cells must ___ signals from multiple sources to fine tune their responses. This is accomplished through _____ proteins which receive multiple inputs
Integrate
Integrator
_____ help reorganize signaling complexes. They contain multiple sites for protein docking and can organize individual components into a signaling ____. This can enhance the speed, efficiency, and specificity of the response
Scaffolds
Complex
____ ____ ____ facilitate the assembly of signaling networks. Each of these compact protein modules bind to a particular structural ____ in the protein with which a signaling protein interacts. This allows signal proteins to bind to one another in multiple combinations resulting in ___ ____ of interactions
Modular biding domains
Motifs
3D networks
____ ____ is the decreased responsiveness that occurs with repeated or chronic exposure to an agonist, it is a general feature of most signaling membrane receptors
Receptor desensitization
_____ ____ is characterized by a decrease in total receptor numbers due to endocytosis and subsequent degradation of the receptors, caused by long term exposure to agonist
Receptor downregulation
Mechanisms to limit signaling:
What are the 4 types of extracellular signaling pathways?
3 types of ion channels:
____-gated
____-gated
_____-gated
Ligand
Voltage
Mechanically
Ligand gated ion channels open and close to allow for regulated ion passage. ______ signaling is when a ligand acts directly on the ion channel (faster). _____ signaling is when a ligand acts on a receptor which indirectly modulates ion channels (slower)
Ionotropic
Metabotropic
Ionotropic and metabotropic signaling play an important role in _____ signaling.
Neuronal
____ gated ion channels open and close in response to changes in membrane voltage
____ gated ion channels open and close in response to physical forces such as stretch, shear, or compression. Associated with multiple sensory functions including hearing and touch
Mechanically
_____ are the largest family of cell surface receptors
G proteins
G protein coupled receptors (GPCRs) interact with heterotrimeric G proteins composed of ___, ___ and ___ subunits
Alpha, beta, gamma
In the ______ state, alpha subunit has GDP bound.
Binding of a signal molecules changes the conformation of the ____ which can then act as a _____ and exchange GDP for GTP. This activates the alpha subunit
Unstimulated
GPCR
GEF (GTP exchange factor)
Once the aloha subunit is activated, this causes the ____ to dissociate into two active units: ____ subunit and the ____ complex
Trimer
Alpha
Beta-gamma
When the alpha subunit binds to target proteins in activates it or inactivates it. Once the alpha subunit hydrolyzes ____ to ____, It dissociates from the target and rebinds to ____ complex, reforming the inactive timeric G protein
GTP
GDP
beta-gamma
Three important pathways regulated by GPCR signaling:
____ ____ pathway produces cAMP and turns on protein kinase A (PKA). PKA regulates ____ and ____ metabolism
Adenylate cyclase
Glycogen
Lipid
______ __ hydrolyzes P1P2 forming IP3 and diacylglycerol (DAG), which raises cytoplasmic _____ and activates protein kinase C (PKC). PKC regulates _____ ____ and ___ ____.
Phospholipase C
Ca++
Cell proliferation
Gene expression
____ monomeric G protein family members (Rho, Rac, and Cdc42) which regulate ____ and cell ____.
Rho
Cytoskeleton
Motility
GPCR continues to act as a GEF for trimeric G protein complexes until turned off. ____ and ____ phosphorylation of GPCRs inhibits their signaling, ____ feedback loop.
_____ also phosphorylates GPCRs allowing ______ to bind and promote ubiquitination and proteolysis
PKA and PKC
GRK (GPCR kinase)
Beta-arrestin
____ ____ signaling usually promotes cell growth, proliferation, differentiation, or survival. The signal ligands are called ___ factors, and usually act locally at low concentrations
Enzyme-linked
Growth
Like G protein linked receptors, enzyme linked receptors are _____ proteins with their ligand-binding domain on the outer surface of the plasma membrane
Transmembrane
Receptors that are tyrosine kinases: ____
Receptors that recruit tyrosine kinases:
Receptors that are serine-threonine kinases:
Receptor guanylyl cyclases:
Receptor tyrosine kinases RTKs regulate three major pathways:
____ —> MAPK: mitogen activated, regulates cell proliferation, gene expression , stress response
_____ —> Ca++/PKC: increase cytoplasmic Ca++, regulates cell proliferation and gene expression
____ —> Akt/PKB, promotes cell survival and inhibits proapoptotic proteins
Ras
Phospholipase C
PI 3-kinase
Receptors that recruit tyrosine kinases: Integrins, ____, and ____
FAK
Src
Cells are connected to the ECM at focal adhesions via _____- transmembrane proteins that bind collagen and laminin externally and microfilaments internally through linking proteins such as ____ and ___.
Integrins
Talin
Vinculin
Focal adhesions have mechanosensing and signal functions which involve two non receptor tyrosine kinases - ____ and ____. These influence cell adhesion, cell motility, and proliferation
FAK
Src
FAK and Src influence numerous other signaling pathways including:
____ is a signaling pathway that integrates information from both GPCR and enzyme linked pathways
mTOR (mechanistic target of rapamycin)
mTOR regulates many processes that are involved in cell ___ and ____ when metabolic and nutritional conditions are favorable. Two complexes ____ and ___.
____ inhibits mTOR activity. ______ inhibits TSC complexes, upregulating mTOR synthesis
Survival
Growth
mTORC1 and mTORC2
TSC (tuberous sclerosis complex)
PKB/Akt
4 signaling pathways associated with proteolytic events:
All 4 what proteolysis pathways lead to changes in ____ ____ and play a role in early ____.
Gene expression
Development
Deregulation of ____ signaling is associated with colorectal cancer
Wnt
_____ signaling play important roles in the regulation of immune system function in adults
NF-kB
Notch signaling ligands are ___ and ___, transmembrane proteins located on adjacent cells. Binding triggers _____ of Notch, releasing the cytosolic ___ inside the cell. The tail goes into the ____ to activate gene expression
Delta and Jagged
Proteolysis
Tail
____ ____ receptors is a type of Intracellular signaling pathway
Nuclear hormone
Ligands of nuclear receptors are small, _____, and membrane permeable. These include: estrogen, progesterone, testosterone, corticosteroids, thyroid hormones, Vitamin D3, retinoic acid. ____ bind to these hormones to help transport them in the circulation
Hydrophobic
Globulins
____ ____ are nuclear hormone receptors whose ligands are currently unknown
Orphan receptors
Some nuclear receptors reside in the cytoplasm and move to the ___ to initiate transcription upon steroid Ligand binding. Others reside in the ____ already bound to DNA and initiate transcription upon metabolite ligand binding
Nucleus
Nucleus
Nuclear hormone receptor activation can result in multiple waves of ___ ___. They can trigger stimulatory and inhibitory ___ ___.
Gene expression
Transcription factors
What types of signaling pathways could this represent:
Nuclear hormone receptor
Estrogen signaling
Ligands are small, hydrophobic molecules
Metabotropic ion channel
Slow and sustained ligand gated ion channel
Involves G protein linked receptors
G protein linked receptor
Enzyme linked receptor
Representing growth factor signaling G1
Ionotropic ion channel
Fast and transient ligand gated ion channel
Proteolysis linked receptor
Notch pathway
Developmental biology is the study of ____ a single cell embryo develops into a multicellular organism with distinct morphology, diverse cell types and organs, and the ability to perform complex tasks
HOW
Development relies on the integration of molecular processes to govern how cells behave in the context of ___ and ____
Time
Space
____ is a process by which one population of cells (inducer) affects the development of another (responder) through cell signaling
Induction
Two types of induction:
______ uses a secreted molecule that diffuses from one cell to another
_____uses direct cell contact
Paracrine
Juxtacrine
_____ is more efficient in impacting populations of cells
Paracrine
Only cells that have the right ____ can respond to a Paracrine signal. Example in eye cells: only the head ectoderm can respond to the optic vesicle, lens is formed in the correct location
Receptor
Mammalian development can be thought of as a series of ____ induction. Neighbor cells produce Paracrine factors that affect other neighbor cells and so on
Sequential
How can cell signaling differentially affect populations of cells?
By forming a concentration gradient
A concentration gradient:
the secreted signaling factors act on distant cells and form a gradient which affects cells differently depending on the _____ of the signaling factors. Secreted signaling factors _____ Intracellular signaling pathways often leading to _____ regulation to derive diverse cell types
Concentration
Activate
Transcriptional
____ _____ signaling pathway:
3 ligands include:____ that all bind to the patched receptor in the plasma membrane and holds another protein SMO. The protein ____ is targeted for proteolytic cleavage in the cytoplasm which enters the nucleus and acts as a _____ repressor. When SHH is present, it binds to patch and prevents the receipt for acting on SMO can now require the protein complex ____ away from the Proteosome. GLI is not cleaved and enters the nucleus as a transcriptional ____.
Sonic hedgehog
SHH, IHH, and DHH
GLI
Transcriptional
Activator
In the absence of SHH, Gli is ____ and acts as a transcriptional ____. When SHH is present, Gli is not ____ and acts as a transcriptional ____.
Cleaved
Repressor
Cleaved
Activator
Cranial caudal axis patterning in the limb is dependent on ____ expressed in the ZPA. ____ creates a ____ and the cells closest to the ZPA get the highest concentration of signal, and will have the highest ____ activator to ____ repressor ratio and will adopt the pinky identity
SHH
SHH
gradient
GLi activator to GLi repressor ratio
Laurin-sandrow syndrome a ZRS associated syndrome show mirror image limbs as a result
_____ signaling is when two different Paracrine signals forming in a gradient can induce different outcomes
Combinatorial
Combinatorial signaling:
The spinal cord has distinct types of neurons along the dorsal/central axis. This pattering is due to ____ ____ ____ of the BMP and SHH ligands
Opposing morphogen gradients
TGFbeta signaling pathway uses _____ to regulate transcription factor localization and activity for differential gene expression
Phosphorylation
TGFbeta :
When ligand binds to the _____ receptor, the receptor phosphorylates the ____ receptor on serines or threonines which activates the _____ ____ activity of the type one receptor. Type one receptor phosphorylates _____ ____. Phosphorylated R-Smad binds to ____ which leads to formation of a ____ protein containing two R-Smads and one co-Smad. This complex then travels to the ____ and binds to Smad consensus sequence in target genes
Type two
Type one
Serine/threonine kinase
Receptor Smads
Smad4
Trimeric
Nucleus
____ are TGFbeta ligands.
BMP
_____ signaling pathway patterns the dorsal spinal cord while _____ patterns the ventral spinal cord. Sets up an opposing BMP SHH gradient
BMP
SHH
Opposing SHH and BMP gradient induces the ____ transcription factors expression along the D/V axis of neural tube
Differential
The dorsal most part of the neural tube that have the highest levels of BMP, express ____ while the ventral part expresses _____
Pax7
Nkx6
Summary of dorsal-ventral patterning of the neural tube:
____ patterning is heavily dependent on the actions and gradients of siffusbke Paracrine signals
Embryo
It is important to affect populations of cells differentially so that embryo development is more ____.
Efficient
Take home message
