cell signaling

RTKs

enzymes that phosphorylate specific tyrosine residues on protein substrates. -involved in regulation of growth, division, differentiation, survival, attachment to the extracellular matrix, and migration of cells.

Extrinsic (receptor-mediated) pathway for apoptosis

When TNF binds to a TNF receptor (TNFR1), the activated receptor binds two different cytoplasmic adaptor proteins (TRADD and FADD) and procaspase-8 to form a multi-protein complex at the inner surface of the plasma membrane. The cytoplasmic domains of the TNF receptor, FADD, and TRADD interact with one another by homologous regions called death domains that are present in each protein. Procaspase-8 and FADD interact by means of homologous regions called death effector domains. Once assembled in the complex, the two procaspase molecules cleave one another to generate an active caspase-8 molecule containing 4 polypeptide segments. Caspase-8 is an initiator complex that activates downstream (executioner) caspases that carry out the death sentence. It can be notes that the interaction between TNF and TNFR1 also activates other signaling pathways, one of which leads to cell survival rather than self-destruction.

extracellular messenger molecules

can travel a short distance and stimulate cells that are in close proximity to the origin of the message, or they can travel throughout the body, potentially stimulating cells that are far away from the source.

G protein-coupled receptors (GPCRs)

huge family of receptors that contain 7 transmembrane (7TM) a helices. -translate the binding of extracellular signaling molecules into the activation of FTP-binding proteins.

60 RTKs 32 non-receptor TKs

human genomes encode nearly _____ RTKs and __ non-receptor TKs

receptor protein-tyrasine kinases

integral membrane proteins that contain a single transmembrane helix and an extracellular ligand binding domain

intrinsic

internal stimuli, such as irreparable genetic damage, lack of oxygen (hypoxia), extremely high concentrations of cystolic Ca2+, viral infection, or severe oxidative stress trigger apoptosis by the _______ pathway

DAG

lipid molecule that remains in the membrane following its formation by PCLB -there it recruits and activates effector proteins that bear a DAG-binding C1 domain (PKC)

endocrine signaling

messenger molecules reach their target cells via passage through the bloodstream. These are also called hormones- they typically act on target cells located at distant sites in the body.

generation of second messengers as a result of ligand-induced breakdown of phospoinositides (PI) in the lipid bilayer

(1) and (2) phosphate groups are added by lipid kinases to phosphatidylinositol (PI) to form phophatidylinositol 4,5-bisphosphate (PIP2). (3) when a stimulus is received by a receptor, the ligand-bound receptor activates a heterotrimeric G protein (4) which activates the effector enzyme PI-specific phospholipase C-B (PLCB) (5) PLCB catalyzes the reaction in which PIP2 is split into 2 molecules: diacylglycerol (DAG) and inoslitol 1,4,5-triphosphate (IP3) ~DAG and IP3 are second messengers (6) DAG recruits the protein kinase C (PKC) to the plasma membrane and activates the enzyme (7) IP3 diffuses into the cytosol (8) where it binds to an IP3 receptor and Ca2+ channel in the membrane of the SER (9) binding of IP3 to its receptor causes release of calcium ions into the cytosol

cell signaling

(1) is initiated with the release of a messenger molecule by a cell that is engaged in sending message to other cells in the body. (2) cells can only respond to an extracellular message if they express receptors that specifically recognize and bind that particular messenger molecule (3) In most cases, the messenger molecule (ligand) binds to a receptor at the extracellular surface of the responding cell. This interaction causes a signal to be relayed across the membrane to the receptor's cytoplasmic domain. 2 major routes by which the signal is transmitted into the cell interior (4) one type of receptor transmits a signal from its cytoplasmic domain to a nearby enzyme (5) which generates a second messenger- the enzyme responsible is called an effector (4a) another type of receptor transmits a signal by transforming its cytoplasmic domain into a recruiting station for cellular signaling proteins. -proteins interact with one another, or with components of a cellular membrane by means of specific types of interaction domains, such as SH3 (6) whether the signal is transmitted by a second messenger or by protein recruitment, the outcome is similar; a protein that is positioned at the top of an intracellular signaling pathway (7) each signaling pathway consists of a series of distinct proteins that operate in sequence (8) signals transmitted along such signaling pathways ultimately reach target proteins (9) involved in basic cellular processes

mechanism of receptor mediated activation (or inhibition) of effectors by heterotrimeric G proteins

(1) ligand binds to receptor, altering its conformation and increasing its affinity for the G protein to which it binds- In GTP bound conformation, the Ga subunit has a low affinity for Gby (2) the Ga subunit releases its GDP, which is replaced by GTP (3) the Ga subunit dissociates from the Gby complex and binds to an effector (may be adenylyl cyclase) (others include C-B and cyclic GMP phosphodiesterase), activating the effector. The Gby dimer may also bind to an effector, such as (PLCb, K+ ion channels, adenylyl cyclase, and PI 3-kinase) (4) activated adenylyl cyclase produced cAMP- second messenger. (5) the GTPase activity of Ga hydrolyzes the bound GTP, deactivating Ga- this results in a conformation change causing a decrease in affinity for the effector and an increase in affinity for the by subunit (6) Ga reassociates with Gby, reforming the trimeric G protein, and the effector ceases its activity. Desensitization (7) the receptor has been phosphorylated by a GRK (8) the phosphorylated receptor has been bound by an arrestin molecule, which inhibits the ligand-bound receptor from activating additional G proteins. The receptor bound to arrestin is likely to be taken up by endocytosis.

receptors that mediate signal transduction

-GPCRs- G protein-coupled receptors -RTKs- receptor protein-tyrasine kinases -ligand gated channels -steroid hormone receptors -other types of receptors including B- and T- cell receptors

can function as extracellular messengers

-amino acid and amino acid derivatives -gases, such as NO and CO -steroids, derived from cholesterol -Eicosanoids -wide variety of polypeptides and proteins

GDIs- guanine nucleotide-dissocation inhibitors

-inhibit release of GDP -keep G proteins inactive

SH2 domain

-mediate a large number of phosphorylation-dependent protein-protein interactions -the specificity of the interactions is determine by the amino acid sequence immediately adjacent to the phosphorylated tyrosine residues.

cross talk

-multiple signals -signal from one pathway affects another pathway -can be pathways regulating or inhibiting one another.

signal convergence

-multiple signals -activation of same pathway or effector (ex) GPCR and RTK, integrins. although these three types of receptors may bind to very different ligands. all of them can lead to the formation of phosphotyrosine docking sites for the SH2 domain of the adaptor protein Grb2 in close proximity to the plasma membrane. The recruitment of the Grb2-Sos complex results in the activation of Ras and transmission of signals down the MAP kinase pathway.

Fundamental Properties of Cells

-sense and respond to environment -communicate with eachother -often involves signal transduction -changing signal into different forms from origin to final point of action

neuronal signaling

-signal delivered to individual cells over long distances -electrical impulse sent along axon to synapse -neurotransmitter released -diffuses across gap to target cell

signal divergence

-single stimulus -multiple responses in same cell -a ligand binding to a GPCR or an insulin receptor -sends signals out along different pathways

advantages of using signal cascade

-transfers signal from point received to site of response -transforms signal into a form that can cause response -amplifies signal ~few signaling molecules generate a large response -distributes signal ~several responses evokes at same time -modulated at each step to fine-tune or adjust response

non-receptor or cytoplasmic protein-tyrasine kinases

...

ligand-mediated dimerization

In the nonactivated state, the receptors are present in the membrane as monomers. Binding of a bivalent ligand leads directly to dimerization of the receptor and activation of its kinase activity, causing it to add phosphate groups to the cytoplasmic domain of the other receptor subunit. The newly formed phosphotyrosine residues of the receptor serve as binding sites for target proteins containing either SH2 or PTB domains. The target proteins become activated as a result of their interaction with the receptor.

epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) or by metabolic regulators such as insulin

RTKs are activated directly by extracellular growth and differentiation factors such as

Adapter proteins

______ contain an SH2 domain and one or more addition protein-protein interaction domains -function as linkers that enable two or more signaling proteins to become joined together as part of a signaling complex.

TNF

______ produced by certain cells of the immune system in response to adverse conditions such as, exposure to ionizing radiation, elevated temperature, viral infection, or toxic chemical agents such as those used in cancer chemotherapy. -senses cell stress

Receptor protein-tyrasine kinases (RTKs)

binding of specific extracellular ligand to an RTK usually results in receptor dimerization followed by activation of the recetpro's protein-kinase domain, present in cytoplasmic region. -upon activation, _________ phosphorylate specific tyrosine residues of cytoplasmic substrate proteins, thereby altering their activity, their localization, or their ability to interact with other proteins within the cell.

calmodulin

calcium binding protein -binds to and activates number of proteins depending on cell type

PTB domain

can bind to phosphorylated tyrosine residues that are usually present as part of an asparagine-proline-X-tyrosine (Asn-Pro-X-Tyr) motif.

receptors

cells can only respond to an extracellular message if they express ____________ that specifically recognize and bind that particular messenger molecule

GEF- guanine nucleotide-exchange factors

changes affinity; stimulates GTP binding

contact-dependent signaling

communicate by direct contact -signal anchored to plasma membrane of signaling cell -binds to receptor protein in plasma membrane of target cell

Heterotrimeric G proteins

consists of 3 different polypeptide subunits, a, b, and gamma. -these proteins are held at the plasma membrane by lipid chains that are covalently attached to the a and gamma subunits

RTKs

control by phosphorylation -phosphorylated by kinases -dephosphorylated by protein phosphotases

GEF GDI GAP

cycling between active and inactive forms aided by accessory proteins -set of regulatory proteins for each type of G protein -proteins that bind to an inactive monomeric G protein and stimulate dissociation of the bound GDP. Once the GDP is released, the G protein rapidly binds a GTP, which is present at relatively high concentration in the cell, inactivating the protein.

GAPs- GTPase activating proteins

most monomeric G proteins- stimulate hydrolysis of the bound GTP, which inactivates the G protein.

signal combinations

multiple signals -combination determines response

PKC- protein kinase C

phosphorylates serine and threonine residues on a wide variety of target proteins important roles: -cellular growth and differentiation -cellular metabolism -cell death -transcriptional activation

Apoptosis

programmed cell death -orderly process characterized by the overall shrinkage in volume of the cell and its nucleus, the loss of adhesion to neighboring cells, the formation of blebs at the cell surface, the dissection of the chromatin into small fragments, and the rapid engulfment of the "corpse" by phagocytosis.

Receptor-mediated dimerization

sequence of events similar to ligand-mediated except that the ligand is monovalent, and consequently, a separate ligand molecule binds to each of the inactive monomers. Binding of each ligand induces a conformational change in the receptor that creates a dimerization interface. The ligand-bound monomers interact through this interface to become an active dimer.

second messenger

small substances that typically activate (or inactivate) specific proteins -depending on chemical structure may diffuse through the cytosol or remain embedded in the lipid bilayer of a membrane

docking proteins

such as IRS -supply certain receptors with additional tyrosine phosphorylation sites. -contain either a PTB domain or an SH2 domain and a number of tyorsine phosphorylation sites.

calcium ions

termed second messengers because they bind to various target molecules, triggering specific responses. -nerve impulse trasmission, secretion, endocytosis, metabolism, cell movement, cell division, regulation of stomata in plants

Src

the SH2 domain of the ___ protein-tyrosine kinase recognizes pTyr-Glu-Ile

Grb2

the adaptor protein ____ contains one SH2 and two SH3 (Src-homoly 3) domains -the SH3 domains bind to proline-rich sequence motifs. The SH3 domains of Grb2 bind constitutively to other proteins, including Sos and Gab.

autocrine signaling

the cell that is producing the messenger expresses receptors on its surface that can respond to that messenger.

paracrine signaling

the messenger molecules travel only short distances through the extracellular space to cells that are in close proximity to the cell that is generating the message -see in tissue where cells are coordinating activity

signal transduction

the overall process in which information carried by extracellular messenger molecules is translated into changes that occur inside a cell is referred to as _________

pH domain

the phosphorylated ring of IP3 can bind to what type of protein domain?

1. RTK 2. GPCRs

the two main switches used to activate signaling molecules in cascade -molecules with inactive and active forms

1. monomeric G proteins (1 subunit) 2. heterotrimeric G proteins (3 subunits)

the two types of G proteins are

STAT

transcription factor that contains an SH2 domain together with a tyrosine phosphorylation site that can act as a binding site for the SH2 domain of another _____ molecule. -play an important role in the function of the immune system

SH2 and PTB

two types of domains found in ligand-mediated and receptor-mediated dimerization

Intrinisic (mitochondria-mediated) apoptosis pathway

various types of cellular stress cause proapoptotic member of the Bcl-2 family of proteins, such as Bax, to become inserted into the outer mitochondrial membrane. Insertion of these proteins leads to the release of cytochrome c molecules from the intermembrane space of the mitochondria. Release is thought to be mediated by pores in the mitochondrial membrane that are formed by Bax oligomers. Once in the cytosol, the cytochrome c molecules forma multi-subunit complex with a cystolic protein called Apaf-1 and procaspase-9 molecules. Procaspase-9 molecules are apparently activated to their full proteolytic capactiy as the result of a conformational change induced by association with Apaf-1. Caspase-9 molecules cleave and activate executioner caspases, which carry out the apoptotic response.

they must express receptors that specifically recognize and bind that particular messenger molecule

what allows cells to respond to an extracellular messenger?

signaling enzymes

when equipped with SH2 domains, these enzymes associate with activated RTKs and are turned on directly or indirectly as a consequence of this association.

clathrin molecules in clathrin coated pits

while bound to phosphorylated GPCRs, to what else can arrestins bind?

Endocrine Signaling

widespread transmission of signal hormones -the messenger molecules reach their target cells via passage through bloodstream