Design principles and control mechanisms of signal transduction networks [Elektronische Ressource] / von Bernd Binder

Bernd Binder

Sujets

• Biologie

Informations

• Publié par: humboldt-universitat_zu_berlin
• Publié le: 01 janvier 2005
• Nombre de lectures: 8
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Design principles and control mechanisms of
signal transduction networks
D I S S E R T A T I O N
zur Erlangung des akademischen Grades
doctor rerum naturalium
(Dr. rer. nat.)
im Fach Biologie
eingereicht an der
Mathematisch-Naturwissenschaftlichen Fakultat I
Humboldt-Universitat zu Berlin
von
Herr Dipl.-Phys.BerndBinder
geboren am 06.08.1970 in Ilshofen
Prasident der Humboldt-Universitat zu Berlin:
Prof. Dr. Mlynek
Dekan der Mathematisch-Naturwissenschaftlichen Fakultat I:
Prof. Thomas Buckhout, PhD
Gutachter:
1. Prof. Dr. Reinhart Heinrich
2. Prof. Dr. Hans-Peter Herzel
3. Prof. Dr. Thomas Hofer
eingereicht am: 31. Januar 2005
Tag der mundlichen Prufung: 31. Marz 2005iiIgnorance more frequently begets con dence than does knowledge: it is those who know
little, not those who know much, who so positively assert that this or that problem will
never be solved by science.
Charles Darwin, The Descent of Man, 1871
iiiivAbstract
Thisworkisbasedonthehypothesisthatsignaltransductionnetworksinlivingcellsare
the result of an evolutionary development which is governed by mutation mechanisms
and natural selection principles. This concerns their structural design as well as kinetic
parameters. Therefore, it can be assumed that these properties have adopted values
which imply certain optimal features with respect to the biological function of signal
transduction.
Based on this working hypothesis, two approaches are presented to investigate the
structural design and control mechanisms of signal transduction networks. Both strate-
gieshaveasacommonresearchobjectivetheexplanationofthesepropertiesofsignalling
networks using certain e ciency criteria.
In the rst approach, covered in chapter 2, a model is developed to analyse the
structural design of signalling networks. A simplied model is used to describe sig-
nalling systems consisting of receptors, kinases and phosphatases. This description in-
cludes important systems like MAP kinase pathways, the PI3K pathway, but also larger
networks which exhibit complex crosstalk activations. Following the hypothesis men-
tioned above, optimisation principles have been applied to determine optimal network
structures regarding certain biological functions. Two dynamic features of signalling
systems are assumed to be crucial for the organism’s surviving capacity: (i) To avoid
autoactivation, e.g. due to stochastic uctuations of receptor ligand or kinase concen-
trations, the signal o -state must be dynamically stable. (ii) The signal output should
be of considerable magnitude, therefore the system should rather amplify than dampen
the signal. To characterise network structures fullling both criteria simultaneously, a
systematic analysis is performed for small networks consisting of up to seven kinases.
The investigations reveal that for such networks the following two design principles hold
true: (i)Withincreasingnetworksizetheconnectivitydecreasesconnotinganincreasing
specicity of kinase activities. (ii) The number of feedback cycles decrease with increas-
ing network size indicating a decreasing tendency of downstream kinases to activate
upstream kinases.
Based on the e ect of small structural perturbations on the dynamic functions, a
quantitative de nition of the robustness of signalling networks is provided. Ratios of
phosphatase and kinase activities maximising this robustness are identied.