Lecture #5 Cell Signaling

-communicate with neighboring cells & distal tissues

-respond/adapt to changes in the extracellular environment

you maintain homeostasis by

a good cellular communication system has

perception of the signal, specificity, response, & termination

perception of the signal

mediated by cell surface or intracellular receptors

specificity

only one or a limited number of receptor types recognize the signal

response

the receptor binds the messenger molecule (ligand) & conveys the message

termination

the signal is switched off by any one of multiple mechanisms (dephosphorylation, degradation, or sequestration of calcium)

cell signaling asks

- to proliferate or differentiate

- to remain attached or migrate

- to survive or die

specificity of receptors (for different types of signals)

helps minimize chaos from cross-talk and signals carrying multiple instructions

redundancy, flexibility, & amplification

advantages of having a multiplicity of signals & signaling intermediates

cell signaling

when information is RELAYED TO THE CELL (through specific receptors) to create a chemical process

transduction

cell signaling relies on the process of signal _______________ (conversion of info/signal into chemical change)

specificity, amplification, adaptation, & integration

signal transduction has what 2 features?

specificity

high affinity & specific interactions between ligand & receptor

amplification

the number of affected molecules increases (geometrically) in a cascade

adaptation

receptor activation triggers feedback mechanisms that DESENSITIZE the cell

integration

cells integrate multiple signals & produce a net outcome

chemicals (protein, amino acids, carbs, lipids, hormones) & physical stimuli (pheromones, tastants, mechanical stimuli)

what signals prompt cellular responses?

travel (vasculature, diffusion, lipophillic)

signals must be relatively small so they are easy to

created/mobilized

signals must be able to be quickly _________________ (from an available substrate or pre-synthesized and/or sequestered ready to be released)

turned off

signals must be able to be _______________ (deactivation, degradation, extrusion, re-sequestration, receptor internalization)

contact-dependent & contact-independent

cell signals can be classified as 2 types

direct

contact-dependent is ___________ signaling that requires cell-cell interaction

contact-dependent

what signaling is important for development, immune responses, & movement of ionic current

indirect

contact-independent is ___________ signaling that relies on soluble mediators

contact-independent

what signaling is important for a myriad of physiological processes & characterized by DISTANCE TRAVELED?

dependent

gap junctions are an example of contact-_______________ signaling

gap junctions

formed by 2 hexagonal structures (connexons) that are ATTACHED end-to-end across 2 adjacent cells

connexins

each connexon (in gap junctions) consist of 6 channels proteins called

diffuse

channels in gap junctions allow small signaling molecules to __________ between the 2 cells

diffusion

direct transfer from one cell to another that allows electrical & chemical processes

electrical

communication between cells when molecules are ions

action potential

diffusion of Na+ and Ca2+ through gap junctions allows __________ to pass through adjacent cardiac muscle cells for synchronous contraction

chemical

communication between cells when molecules are small messengers (like cAMP)

dependent

juxtacrine signaling is an example of contact-____________ signaling

juxtacrine signaling components

signal: NO soluble signal

specificity: receptors

response: opening of ion channels, cell attachment, changes in growth, motility, increases in calcium, gene expression

termination: cell detachment

immune signaling

what signaling is contact-dependent & involves antigen presentation or cellular killing?

independent

paracrine, endocrine, autocrine, & intracrine signaling are example of contact-________________ signaling

endocrine

ligand travels LONG DISTANCES to target cells thru the blood stream (receptor far)

paracrine

ligands travel to NEIGHBORING CELLS within the same tissue (receptor close- close distance)

autocrine

ligand is both produced & utilized by the SAME cell

intracrine

ligand never leaves the cell (synthesized & acts entirely within the intracellular environment)

ligand-gated ion channels, enzyme-linked receptors, g protein-coupled receptors, & nuclear receptors

what are the 4 primary classes of membrane receptors?

ligand-gated ion channel receptors

**deal with changes in MEMBRANE POTENTIAL

excitable

ligand-gated ion channel receptors are receptors critical for _______________ tissues (nervous, cardiac)

ions

ligand-gated ion channel receptors prompt rapid changes in the movement/redistribution of ______ across the membrane

membrane potential

difference in voltage across the PM (always given as voltage inside the cell relative to the outside)

resting potential

difference in voltage across the PM when the cell is at rest

electrochemical gradients

movement of ions is governed by what gradients?

heteromeric/homomeric oligomers (4-5 subunits)

ligand-gated ion channel receptors have a structure of

conformational change

ligand binding prompts what change in the channel that opens/closes it?

open channels

ions move down their electrochemical gradient & change membrane potential

closed channels

ions no longer move & still change membrane potential

opening of voltage-gated ion channels & generation of an action potential

movement of ions cause localized changes (in charge) across the membrane which prompts

acetylcholine

what is a common ligand in ligand-gated ion channel receptors?

ligand-gated ion channel receptor

nicotinic acetylcholine receptor is what type of membrane receptor?

nicotinic acetylcholine receptor

-critical for synaptic transmission at the neuromuscular junction

-binding of acetylcholine OPENS channel

-depolarization of the muscular membrane

reception, transduction, & cellular response

what are the 3 basic stages of membrane receptor signaling?

reception

ligand binds receptor

transduction

receptor structure CHANGES & intracellular molecules activated

cellular response

changes in cellular physiology and/or gene expression

1st messenger

ligand that binds/activates membrane receptor

effector proteins

protein ACTED ON by the membrane receptor (receptor/associated proteins activate effector proteins)

2nd messenger

intracellular molecules produced by an extracellular signal (activation of intracellular processes)

post-translational

membrane receptor signaling often results in what modifications to proteins?

post-translational modications

proteolysis, glycosylation, isoprenylation, ubiquitylation, sumoylation, methylation, phosphorylation, & acteylation

phosphorylation

-occurs on tyrosine, serine, threonine

-alters protein function (activates/inactivates proteins)

acetylation & methylation

-occurs on lysine & arginine

-epigenetics/gene regulation/chromatin remodeling

ubiquitination

-occurs on lysines

-targets proteins for degradation & recycling

enzyme-linked receptors

-single-pass transmembrane receptor

-receptor engagement activates enzymatic domain (ligand binding prompts dimerization)

-enzyme might be a domain in the receptor protein OR a linked SECONDARY protein

enzyme-linked receptor structure

single polypeptide that crosses the membrane once (dimeric or dimerize after activation)

receptor tyrosine kinase (RTK) pathway

1. ligand binding causes structural change in the receptor

2. receptors dimerize

3. initiation of the function for catalytic, tyrosine kinase domain

4. receptor autophosphorylation & phosphorylation of cellular proteins

receptor dimerization

what initiates the function of the catalytic, tyrosine kinase domain in RTKs?

RTK examples

EGF, PDGF, insulin, insulin-like growth factor

ligand

the receptors are only active when they dimerize; with no ________ bound, the receptors cannot dimerize

transphosphorylation

change in conformation permits ATP to bind & ______________ of the opposite half of the dimer pair

MAPK/MEK, PI3K-Akt, JAK-STAT, Rac-Rho, & PLCy-PKC

RTKs activates many downstream signaling molecules involved in cancer like

growth factor receptors

RTKs are mainly what kind of receptors?

MAPK pathway

ligand binds to activate RTK, GRB2 binds to RAS & SOS, which activates RAF, which activates MAPK (DS signal is relayed by activated signaling proteins)

EGFR pathway

Ras->Raf->MAPK

tyrosine kinase domain goes straight into STAT signaling

PI3K->Akt (PTEN can inhibit)->mTOR

*all lead to cell proliferation, survival, migration, adhesion, & differentiation

cancer

mutations in the EGFR pathway are favorable for the development of what?

cancer pathway example

dimerizes & proceeds Grb2 & Sos-> Ras-> Raf-> MEK-> ERK-> DNA

Ras

mutaions in _____ lead to cancer (pancreatic, papillary thyroid, colon, non-small cell lung)

flexibility & diversity of response

separating the ligand binding (receptor) domain from the effector (kinase) domain has advantages for

JAK

protein that is constitutively associated with cytokine receptors (soluble Tyr kinases)

kinase

receptor region is composed dimeric/trimeric subunits, but the receptor itself has no ________ activity

tyrosine kinase-associated receptor pathway

1. ligand binds & changes structure of receptor

2. receptor dimerizes & the associated tyrosine kinases become ACTIVATED

3. kinase phosphorylates downstream effector proteins

examples of tyrosine kinase-associated receptors

cytokines, growth hormone, prolactin

STAT

protein family (signal transduction and transcription) & latent transcription factors (do not act as TFs until activated)

JAK/STAT pathway

1. JAKs phosphorylate the receptor, creating docking sites for STATs

2. STATs bind to cytokine receptor & JAKs phosphorylate them (they're close)

3. STATs break away from receptor, dimerize, & enter nucleus (where they bind DNA, promote cell proliferation, migration, & cell survival)

SOCS

small inhibitory protein (suppressors of cytokine signaling)

block the catalytic domain of JAK & trigger ubiquitination/degradation of the receptor/STAT proteins (SOCS binds to JAK, so STAT can't get in)

how does SOCS work?

SOCS inhibits JAK from phosphorylating STAT, turns of STAT signaling

why is there no runaway cell proliferation under normal conditions in the JAK/STAT pathway?

receptor tyrosine phosphatase pathway

1. ligand binding causes structural change of receptor

2. these structural changes activates the tyrosine PHOSPHATASE domain

3. the enzymatic domain participates in the dephosphorylation of DS proteins

receptor tyrosine phosphatase examples

CD45 on T & B cells

CD45

negative regulator of Lck

phosphorylation

CD45 is activates small cytosolic TKs (Lyn, Fyn) by removing ______________ on an inhibitory tyrosine

activates; inhibits

**CD45 ___________ Lyn,Fyn & __________ Lck

receptor guanylyl cyclase pathway

1. ligand binding causes structural change in receptor

2. guanylyl cyclase domains become activated

3. GTP is converted to cGMP

4. cGMP activates PKG (phosphorylates proteins)

receptor guanylyl cyclase examples

atrial natriuretic factor, nitric oxide

receptor serine/threonine kinase pathway

1. requires cooperation between type I & II receptors

2. type II receptors recognize the ligand & prompts the receptor to form a complex with type I receptor

3. autophosphorylation of type I receptor & phosphorylation of DS effector proteins