Signaling transduction tutorial

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Signaling transduction tutorial

August 12, 2014 by larryhbern

Signaling transduction tutorial

Larry H. Bernstein, MD, FCAP, Reporter and Curator
Leaders in Pharmaceutical Intelligence

http://pharmaceuticalintelligence.com/8-10-2014/Signaling transduction tutorial

This portion of the discussion is a series of articles on signaling and signaling pathways. Many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different. I considered placing this after the discussion of proteins and how they play out their essential role, but this is quite a suitable place for a progression to what follows. This is introduced by material taken from Wikipedia, which will be followed by a series of mechanisms and examples from the current literature, which give insight into the developments in cell metabolism, with the later goal of separating views introduced by molecular biology and genomics from functional cellular dynamics that are not dependent on the classic view. The work is vast, and this discussion does not attempt to cover it in great depth. It is the first in a series. This discussion, in particular is a tutorial on signaling transduction that was already available, and relevant. One may note that all of the slides used herein were also used in the previous blog, but in a different construction. I shall tweak the contents, as I find helpful.

Signaling and signaling pathways
Signaling transduction tutorial.
Carbohydrate metabolism
Lipid metabolism
Protein synthesis and degradation
Subcellular structure
Impairments in pathological states: endocrine disorders; stress hypermetabolism; cancer.

Signal Transduction Tutorial

The goal of this tutorial is for you to gain an understanding of how cell signaling occurs in a cell. Upon completion of the tutorial,

you will have a basic understanding signal transduction and
the role of phosphorylation in signal transduction.

You will also have detailed knowledge of

the role of Tyrosine kinases and
G protein-coupled receptors in cell signaling.

Description of Signal Transduction

As living organisms

we are constantly receiving and interpreting signals from our environment.

These signals can come

in the form of light, heat, odors, touch or sound.

The cells of our bodies are also

constantly receiving signals from other cells.

These signals are important to

keep cells alive and functioning as well as
to stimulate important events such as
cell division and differentiation.

Signals are most often chemicals that can be found

in the extracellular fluid around cells.

These chemicals can come

from distant locations in the body (endocrine signaling by hormones), from
nearby cells (paracrine signaling) or can even
be secreted by the same cell (autocrine signaling).

intercellular signaling

http://www.hartnell.edu/tutorials/biology/images/intercellularsignaling.jpg

Signaling molecules may trigger any number of cellular responses, including

changing the metabolism of the cell receiving the signal or
result in a change in gene expression (transcription) within the nucleus of the cell or both.

Overview of Cell Signaling

Cell signaling can be divided into 3 stages.

Reception: A cell detects a signaling molecule from the outside of the cell. A signal is detected when the chemical signal (also known as a ligand) binds to a receptor protein on the surface of the cell or inside the cell.
Transduction: When the signaling molecule binds the receptor it changes the receptor protein in some way. This change initiates the process of transduction. Signal transduction is usually a pathway of several steps. Each relay molecule in the signal transduction pathway changes the next molecule in the pathway.
Response: Finally, the signal triggers a specific cellular response.

signal transduction_simple

http://www.hartnell.edu/tutorials/biology/images/signaltransduction_simple.jpg

Reception

Signal Transduction – ligand binds to surface receptor

Membrane receptors function by binding the signal molecule (ligand) and causing the production of a second signal (also known as a second messenger) that then causes a cellular response. These types of receptors transmit information from the extracellular environment to the inside of the cell

by changing shape or

conformational-rearrangements

Enzyme_Model allosterism

by joining with another protein
once a specific ligand binds to it.

Examples of membrane receptors include

G Protein-Coupled Receptors and

membrane_receptor_g protein

Receptor Tyrosine Kinases.

activation of receptor Tyrosine Kinase

http://www.hartnell.edu/tutorials/biology/images/membrane_receptor_tk.jpg

Intracellular receptors are found inside the cell, either in the cytopolasm or in the nucleus of the target cell (the cell receiving the signal).

Chemical messengers that are hydrophobic or very small (steroid hormones for example) can

pass through the plasma membrane without assistance and
bind these intracellular receptors.

Once bound and activated by the signal molecule,

the activated receptor can initiate a cellular response, such as a
change in gene expression.

Note that this is the first time that change in gene expression is stated. Is the change in gene expression implication of a change in the genetic information – such as – mutation? That does not have to be the case in the normal homeostatic case. This might only be

a change in the rate of a transcription or a suppression of expression through RNA.

intracellular_receptor_steroid

http://www.hartnell.edu/tutorials/biology/images/intracellular_receptor_steroid.jpg

Transduction

Since signaling systems need to be

responsive to small concentrations of chemical signals and act quickly,
cells often use a multi-step pathway that transmits the signal quickly,
while amplifying the signal to numerous molecules at each step.

Signal transduction cascades amplify the signal output

Steps in the signal transduction pathway often involve

the addition or removal of phosphate groups which results in the activation of proteins.
Enzymes that transfer phosphate groups from ATP to a protein are called protein kinases.

Many of the relay molecules in a signal transduction pathway are protein kinases and

often act on other protein kinases in the pathway. Often
this creates a phosphorylation cascade, where
one enzyme phosphorylates another, which then phosphorylates another protein, causing a chain reaction.

phosphorylation-cascade

Also important to the phosphorylation cascade are

a group of proteins known as protein phosphatases.

Protein phosphatases are enzymes that can rapidly remove phosphate groups from proteins (dephosphorylation) and thus inactivate protein kinases. Protein phosphatases are

the “off switch” in the signal transduction pathway.

Turning the signal transduction pathway off when the signal is no longer present is important

to ensure that the cellular response is regulated appropriately.

Dephosphorylation also makes protein kinases

available for reuse and
enables the cell to respond again when another signal is received.

Kinases are not the only tools used by cells in signal transduction. Small, nonprotein, water-soluble molecules or ions called second messengers (the ligand that binds the receptor is the first messenger) can also

relay signals received by receptors on the cell surface
to target molecules in the cytoplasm or the nucleus.

membrane protein receptor binds with hormone

insulin receptor and and insulin receptor signaling pathway (IRS)

binding-proteins-and-bioavailable-25-hydroxyvitamin-d

Examples of second messengers include cyclic AMP (cAMP) and calcium ions.

membrane_receptor_g protein

http://www.hartnell.edu/tutorials/biology/images/membrane_receptor_gprotein.jpg

Response

Cell signaling ultimately leads to the regulation of one or more cellular activities. Regulation of gene expression (turning transcription of specific genes on or off) is a common outcome of cell signaling. A signaling pathway may also

regulate the activity of a protein, for example

ion-transporters-and-channels-in-mammalian-choroidal-epithelium

Ca(2+) and contraction

transepithelial-electrogenic-ion-transport

calcium release flux

opening or closing an ion channel in the plasma membrane or
promoting a change in cell metabolism such as catalyzing the breakdown of glycogen.

Signaling pathways can also lead to important cellular events such as

cell division or apoptosis (programmed cell death).

ubiquitylation-is-a-multistep-reaction.

Involvement of VSMCs apoptosis in fibrous plaque rupture.

G- Protein-Coupled Receptor

membrane_receptor_g protein

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

Signal Transduction Tutorial by Dr. Katherine Harris is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

Funded by the U.S. Department of Education, College Cost Reduction and Access (CCRAA) grant award # P031C080096.

http://creativecommons.org/licenses/by-nc-sa/3.0/

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