Cell Signaling Flashcards by Lily Nunvar

_____ 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

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____ ____ (_____): 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

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A ____ is a signaling molecule produced by one cell that binds to a receptor on either the same or another cell

Ligand

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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

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Signal transduction results in the activation or release of other small Intracellular molecules called ____ ___. Ex: cAMP, cGMP, IP3, DAG, Ca++

Second messengers

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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

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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

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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

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____ ____ loops occur if an upstream molecule regulates a downstream target through two or more separate mechanisms or pathways

Feed forward

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___ ___ loops amplify a response through the ability of a product to increase the activity of an earlier component of the pathway

Positive feedback

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____ ___ loops limit a response by the ability of a product to inhibit the activity of an earlier component of the pathway

Negative feedback

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____ ____ 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

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______ ____ 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

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What mechanisms determine weather the response is graded or switch like?

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The concentration of a molecule can be adjusted rapidly only if it’s half life is ____

Short

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The response increases with an ____ in the number of effector molecules that must bind simultaneously to activate a target

Increase

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Switch like functions in a cell signaling pathway can involve _____ or ____.

Phosphorylation
G proteins

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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

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Many cells must ___ signals from multiple sources to fine tune their responses. This is accomplished through _____ proteins which receive multiple inputs

Integrate
Integrator

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_____ 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

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____ ____ ____ 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

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____ ____ 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

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_____ ____ 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

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Mechanisms to limit signaling:

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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