3) Cell Receptors, Ola Elgaddar

LAB EVALUATION OF CELL DISORDERS

3) Receptors

Ola H. Elgaddar

MD, PhD, CPHQ, LSSGB Lecturer of Chemical Pathology

Medical Research Institute Alexandria University

[email protected]

Signal Transduction Systems:

-Signal transduction is the chemistry that

allows communication at the cellular level.

- Cells sense signals from the extracellular

and intracellular environments, as well as

directly from other cells.

- Cells respond to these signals in a variety

of ways, primarily by modifying protein

levels, activities, and location.

- Protein levels are controlled by rates of

transcription, translation, and proteolysis,

whereas protein activities are affected by

covalent modifications and non-covalent

interactions with other proteins and small

molecules.

- Most signals are initiated by ligands and are

sensed by the receptors to which they bind.

- Binding of a ligand to a receptor stimulates the

activities of proteins necessary to continue the

transmission of the signal through the formation of

multi-protein complexes and the generation of

small-molecule second messengers.

- Integration of signals from multiple pathways

determines the cell's ultimate response to

competing and complementary signals.

Signals (Ligands):

-Signal transduction pathways

respond to different types of stimuli.

- Molecules that initiate signaling

cascades include proteins, amino

acids, lipids, nucleotides, gases, and

light.

Several classifications for signals!

- Some signals are continuous, such as

those sent by the extracellular matrix,

whereas others are episodic, like the

secretion of insulin by pancreatic cells

in response to increases in blood

glucose.

- Signaling molecules originate from a

variety of sources. Some, such as

neurotransmitters, are stored in the

cell and are released to provide

communication with other cells under

specific conditions. Other ligands are

stored outside the cell (e.g., in the

extracellular matrix) and become

accessible in response to tissue damage

or remodeling.

- Traditionally, signals have been

divided based on the cell of origin

into those that affect distant cells

(endocrine), nearby cells

(paracrine), or the same cell

(autocrine).

Receptors:

-The plasma membrane of eukaryotic cells

serves to insulate the cell from the outside

environment, but this barrier must be breached

to transmit signals of extracellular origin.

- This fundamental problem of transmitting

extracellular signals is solved in two ways:

1. Signals cross the plasma membrane by

activating transmembrane receptors

2. Using ligands that are membrane permeable

Receptors in Signal Transduction:

1) Receptor Tyrosine Kinases

2) Serine-Threonine Kinase Receptors

3) Receptor Phosphotyrosine Phosphatases

4) G protein-coupled receptors

5) Notch Family of Receptors

6) Guanylate Cyclases

7) Tumor Necrosis Factor Receptor Family

8) WNT Receptors

9) Nuclear Receptors

10)Adhesion Receptors


-Receptor tyrosine kinases are transmembrane

proteins that have an extracellular ligand-binding

domain, a transmembrane domain, and a

cytoplasmic tyrosine kinase domain.

- The ligands for these receptors are proteins or

peptides

- Most receptor tyrosine kinases are monomeric,

but members of the insulin-receptor family are

heterotetrameres in which the subunits are linked

by disulfide bonds.

- Examples of tyrosine kinase receptors include the

insulin receptor, the platelet-derived growth factor

(PDGF) receptor, the EGF receptor family, and the

fibroblast growth factor (FGF) receptor family.

- Activation of receptor tyrosine kinases generally

requires tyrosine phosphorylation of the receptor.

In the case of the insulin receptor, an insulin-

stimulated conformational change activates the

kinase. Most other tyrosine kinases are activated

by ligand-induced oligomerization, which brings

the kinase domains of distinct molecules into close

proximity so that they cross-phosphorylate.









8) WNT Receptors



2) Serine-Threonine Kinase

Receptors

-The TGF-β receptors are transmembrane

proteins with intrinsic serine-threonine kinase

activity.

- There are two types; type I & II

- TGF-β ligands are dimers that bind to and

oligomerize type I and type II receptors.

- The type II receptors seem to be

constitutively active but do not

normally phosphorylate substrates,

whereas the type I receptors are

normally inactive

- Ligand-mediated dimerization of

the type I and type II receptors causes

the type II receptor to phosphorylate

the type I receptor









8) WNT Receptors



3) Receptor Phosphotyrosine

Phosphatases

- Protein tyrosine phosphatases (PTPs) are a

group of enzymes that remove phosphate

groups from phosphorylated tyrosine residues on

proteins.

- They have an extracellular domain, a single

transmembrane-spanning domain, and

cytoplasmic catalytic domains.

-The extracellular domains of some receptor

tyrosine phosphatases contain fibronectin and

immunoglobulin repeats, suggesting that these

receptors may recognize adhesion molecules as

ligands.

- Functional and structural evidence suggests that

the phosphatase activity of some of these receptors

is inhibited by dimerization

- Ligand-dependent dimerization could cause

constitutively active tyrosine phosphatases to lose

activity, enhancing signals emanating from tyrosine

kinases.

- These enzymes are key regulatory components in

signal transduction pathways (such as the MAP

kinase pathway) and cell cycle control, and are

important in the control of cell growth,

proliferation and differentiation









8) WNT Receptors



4) G protein-coupled

receptors (GPCRs)

-GPCRs are by far the most numerous receptors as

they encode the light, smell, and taste receptors.

-Examples include thrombin, neurotransmitters and

EGF receptors.

- Structurally GPCRs are characterized by an

extracellular N-terminus, followed by seven

transmembrane (7-TM) α-helices (TM-1 to TM-7)

connected by three intracellular (IL-1 to IL-3) and

three extracellular loops (EL-1 to EL-3), and finally

an intracellular C-terminus

- Intramolecular bonds involving

residues in the transmembrane or

juxtamembrane regions keep GPCRs in

an inactive conformation.

- In the inactive state, the receptor is

bound to a heterotrimeric G protein,

which is also inactive.

- Agonist binding causes a

conformational change that stimulates

the guanine nucleotide exchange activity

of the receptor. Exchange of guanosine

triphosphate (GTP) for guanosine

diphosphate (GDP) on the heterotrimeric

G proteins initiates signaling.









8) WNT Receptors




- The Notch receptor has a large extracellular domain,

a single transmembrane domain, and a cytoplasmic

domain.

-Ligands for the Notch receptor are proteins expressed

on the surface of adjacent cells, and activation results

in two proteolytic cleavages of Notch, releasing its

cytoplasmic region as a soluble signal

- This fragment moves to the nucleus, where it

complexes with a transcriptional repressor, relieving

its inhibitory effects and stimulating transcription









8) WNT Receptors




- Guanylate cyclases (GCs) convert GTP to cGMP

upon activation.

There are two forms of GCs:

Membrane GCs are receptors for atrial natriuretic

hormone, peptides that regulate intestinal secretion

and are necessary for regulating cGMP levels for

vision.

Soluble GCs are activated by nitrous oxide. These

receptors are widely expressed and regulate vascular

tone and neuron function.









8) WNT Receptors



7) Tumor Necrosis Factor Receptor

Family

- The TNF family of receptors has a cysteine-rich

extracellular domain, a transmembrane domain, and a

death domain in the cytoplasm

-Receptors undergo oligomerization after ligand binding

- Stimulation of the receptor leads to recruitment of

cytoplasmic proteins that bind to each other and the

receptor through death domains, thereby activating a

protease, caspase 8 that initiates apoptosis

- Under some conditions, however, TNFRs may

stimulate antiapoptotic signals









8) WNT Receptors



8) WNT Receptors

-The wnt family of growth and differentiation

factors consists of small proteins that bind to cell

surface receptors of the Frizzled family

-These receptors resemble GPCRs but utilize a

unique mechanism of signal transduction.

- Wnt proteins got their name from two of the first

to be discovered:

Wingless (wg) in Drosophila and its homolog

Int-1 in mice

- Binding of wnt to the receptor suppresses a

kinase cascade complex that involves many

proteins.

- This complex mediates phosphorylation and

ultimately proteosome-depend degradation of β-

catenin

- Suppression of β-catenin degradation in

response to wnt allows β-catenin to accumulate

in the cell and to migrate into the nucleus where

it regulates genes involved in cell growth

regulation









8) WNT Receptors




-Ligands for nuclear receptors diffuse into the

cell and bind their receptors on the nucleus.

- The ligands include steroids, eicosanoids,

retinoids, and thyroid hormone.

- The receptors are transcription

factors that have both DNA- and

ligand-binding domains.

-The unliganded receptor is bound to

heat-shock proteins that are

dissociated after ligand binding.

-Release from the chaperone complex

and ligand association lead to binding

of the receptor to cofactors and DNA

to regulate transcription.

Chaperones are proteins that assist

the non-covalent folding or unfolding

and the assembly or disassembly of

other macromolecular structures, but

do not occur in these structures when

the structures are performing their

normal biological functions









8) WNT Receptors



10) Adhesion Receptors

- Cell adherence, either to the extracellular matrix or to

other cells, is mediated by receptors that function

mechanically and stimulate intracellular signaling

pathways, primarily through tyrosine kinases

- Integrins mediate adherence to extracellular matrix

and are composed of heterodimers of α and β subunits.

- There is a ligand-binding site that binds the

extracellular matrix and a cytosolic domain that binds

the cytoskeleton.

- Interaction between the extracellular domain of

integrins and an extracellular ligand generate a variety

of signals.

- The interaction leads to clustering of integrins and the

rapid tyrosine phosphorylation of proteins at the

cytoplasmic face.

- Focal adhesion kinase (FAK) is an effector in

integrin-mediated responses.









8) WNT Receptors



SIGNALING!!

Health & Medicine

3) Cell Receptors, Ola Elgaddar