Signal Transduction

BIO202

Aurnab Ghose; 150121

X1 X2 X3

Signal 1 Signal 2 Signal 3 Signal 4 Signal N

Xm

gene 1 gene 2 gene 3 gene 4 gene 5 gene 6 ... gene k

Environment

Transcription factors

genes

...

...

An environmental sensing mechanism

Wyrick and Young, 2002

Transcription factor activities form the internal representation of the environmental states

The colored circles represent distinct transcriptional activators. The rectangular ovals represent potential target genes The color of the rectangular oval indicates which transcriptional activator is regulating its expression in response to the environmental stimulus; in addition, arrows point from each transcriptional activator to its regulated genes.

What is Signal Transduction?

It is the process of converting signals into responses

i.e., receiving, interpreting, processing, amplifying and responding to information

Signal transduction •  Conversion of information from one

form into another

Evolution and Expansion of Intracellular Signaling

Autocrine Paracrine Endocrine

Forms of secreted molecules-mediated signaling

Components of Signal Transduction

SIGNAL

RESPONSE

DISCRIMINATOR

TRANSDUCER

AMPLIFIER

Discriminator

Transducer

Amplifier

Effector

Martin Rodbell applied this analogy to signal transduction in biology

Extracellular signaling molecules fall into 2 classes:

1.  Molecules that are too large or too hydrophilic to cross the plasma membrane - rely on membrane receptors

2.  Molecules that are small enough or hydrophobic and pass through the membrane - directly activate intracellular enzymes or bind cytosolic receptors

(e.g. NO; steroids)

Cell surface receptors fall into 3 main classes

1.  Ion channel-linked receptors

2.  G-protein-linked receptors (GPCRs)

3.  Enzyme-linked receptors

Cell surface receptors fall into 3 main classes

Major Signal Transduction Pathways

Mitogen Activated Protein Kinase (MAPK) pathway : A typical example

(receptor – ligand interaction)

MAPK signalling cascade

From relatively simple biochemical pathway – How is specificity achieved?

How is sensitivity achieved?

How is reliability achieved (robustness)?

How is pleiotropy in biological function achieved? (integration of multitude of inputs)

Amplitude and duration of the signal flux

Combinatorial integration of network crosstalk Versatility of component function

Pleiotropy of biological function Not possible to have a unique receptor or a signal transduction unit for every input. The structure and the dynamics of the system will matter

Combinatorial integration of network crosstalk Versatility of component function

Protein based information flux in order to act as a signal transduction system requires:

(receptor – ligand interaction)

K1 > K2 > K3 > K4

Allosteric Regulation

The regulation of an enzyme or other protein by the binding of an effector molecule at a site other than the protein's active site.

Koshland’s sequential model

Specificity

Specificity

There is sea of ‘similar’ molecules, then ….

Kinetic Proofreading *

Equilibrium binding considerations suggest ~100x higher error rate

Note: 3-tiered Dual-phosphorylation

Is more better than less?

Why do MAPKs have a 3 tiered structure? Does dual phosphorylation requirement of MAPKs for activation have an advantage?

Sensitivity

-  Signal amplification (modest)

-  More regulatory interfaces

-  Multistep ultrasensitivity

Why do MAPKs have a 3 tiered structure?

Sensitivity

Multistep Ultrasensitivity

Sensitivity Specificity

Noise filtration Switch-like responses for small range of filtered stimuli

Does dual phosphorylation requirement of MAPKs for activation have an advantage?

-  Coincidence detection (specificity)

-  Ultrasensitivity

Sensitivity Specificity

Regulatory Influences of MAPK pathways

Inhibitory proteins Phosphatases

Sensitivity Specificity

Feedback loops

Sensitivity Specificity Positive feedback loops can enhance sensitivity

(EGF/EGFR > ROS > Inhibition of phosphatases)

Green arrows: activation Red blunt-ended lines: inhibition

Scaffold proteins: localization/specificity

Specificity

MAPK signalling cascade

Specificity

Network view of signal transduction

Patterns of connectivity in “real networks” are called network motif’s

Nodes are signalling proteins Edges: Directed interactions (covalent modification of another protein)

How to find network motif’s in a network? Compare “real” and “randomized” networks (randomized: same # of nodes and edges as real networks but the connections are made randomly)

Network motif‘s are patterns that occur more significantly (statistically) in real than randomized networks Network motif’s are patterns conserved through evolution Mutations can randomly change edges (remove or add) Edges need to be constantly selected in order to prevent randomization

Diamond motif

Seen uniquely in signal transduction networks and not in transcriptional networks

Multi-layer patterns in signalling networks show connections from one layer to the next (no connections two-layers down, for example) Structure is similar to patterns in AI and Artificial neural networks

The question of Integration: can Neural Networks help?

Thickness of arrows indicate connection weight

A neural network trained by evolution! Neural networks can be trained to recognize specific input patterns and generate corresponding specific output patterns

Specificity

Large interactive networks (incl. Neural Networks) display Robustness ie, can maintain function despite external and internal perturbations

Robustness is essential for:

Appropriate communication Generating appropriate response Preventing cellular malfunction

Robustness