1. Mechanochemical Signal Transduction and
Role of Mechanical forces:
Various Aspects and its Clinical Implications
SUCHI AGRAWAL
11610001
MSc Biotechnology,II Yr
SEMINAR TERM PAPER
2. A few simple things that
intrigued me into this
aspect of biology…….
3. Do animals know at a physiological level how
much they weigh and
if so, do they make homeostatic adjustments
in response to
changes in body weight?They
should of course!But how?
Ever wondered how the continuous
pressure experienced by the cells
when we sit on a computer and write
for extended periods gets dissipated
and filtered out…not causing any
tissue deformation?
4. A and B.Shear forces acting directly on membrane proteins or tugging forces on cytoskeleton
causes associated Stress activated ion channels to open up like a ‘GATED SPRING’.
C.Effect of tensional forces on a substrate displaces it from the enzyme’s active site.
D.Stretch on a folded polypeptide opens up embedded/hidden residues only to be exposed and
bound by an appropriate entity.
E.Compression and Relaxation forces alter the length of an actin filament by addition of new
subunits.
NANOSCALE EFFECTS
(Ingber E Donald,2006)
5. EVOLUTIONARY HISTORY:Bioluminescence;explanation for
Glowing Seas suggested
How suspended Dinoflagellates and adherent endothelial cells show conserved signaling mechanism to
Shear stress involving G proteins (the present hypothesis)?
FUTURE DIRECTION.Feasibility of a designing a live imaging system by using this shear stress dependent
Lucifease Bioluminescence.Study of Scintillon design necessary!
(http://www.sciencedaily.com/releases/2011/10/111019190823.htm)
7. POSTNATAL LUNGS:
Lung aeration causes surface tension to form which greatly increases lung recoil
leading to a reduction in interstitial tissue and pleural pressures as well as lung
expansion inspite of presence of Surfactant!
(Hooper.B Stuart et al.2005)
9. 1.Greater insights into ‘Chronic diseases
of lung’ due to Mechanical Ventilation at
premature birth.Improvement by
additional substitution with innumerable
growth factors made on mechanical
stress.
2.Future direction for treatment of
Emphysema:Stress induced extracellular
matrix expression and balancing of
metalloprotease production.
(http://www.cts.usc.edu/lungvolumereductionsurgery.html)
11. Single-molecule force spectroscopy assay for
the detection of single reduction events by the
enzyme Trx(Thioredoxin)
‘Finger print‘ characteristic of folding pattern of protein.
(George Alegre et al.2010)
15. Ectopic expression of ‘Twist’ due to applied forces
on Drosophila leads to production of Beta-actinin.
Failure of embryonic development, due to
disruption of the dorsal-ventral axis.
Crosstalk between Wnt signaling and mechanical
cues in skeletal patterning and embryogenesis.
(Kastanon Irinka,2001)
16. FUTURE DIRECTON:Study effect of
mechanical stress on cell adhesion
factors ‘in isolation from effect of
interdependent soluble
mitogens/chemical cues’
Motility factors cause protusions to develop
from a cell from the corners of the matrix!
17. A new Vision towards driving Human Stem Cell
Differentiation:Implication for Translational
Medicine and hESC Therapy
Signal transduction pathways like Wnt and Hedgehog (Hh) in the PRIMARY
CILIA are crucial for embryological development and tissue differentiation.
The existence of primary cilia and the localization of signaling components in
undifferentiated hESCs establishes a mechanistic basis for the regulation of
hESC differentiation.
Picture:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265400/figure/fig1/
19. Tumour Formation
54 Copyright c 2004 Tech Science Press MCB, vol.1, no.1, pp.53-68, 2004
linear way in which soluble angiogenic factors activate
growth signaling cascades in endothelial cells that lead
to the progressive elongation of new capillary blood ves-
sels. The reality is that this process is much more com-
plex as neighboring regions of the same growing tissue
often simultaneously exhibit different behaviors. For in-
stance, early analysis of tissue remodeling [Clark and
Clark (1938)] revealed that while one capillary sprout
may grow in response to angiogenic stimulants, another
capillary tube right next to it, will remain quiescent and
differentiated, while yet another undergoes retraction and
dies through a process of programmed cell death known
as apoptosis. And all of this happens in a tissue microen-
vironment that we now know is saturated with many sol-
uble mitogens. Moreover, establishment of similar lo-
cal differentials of cell growth, differentiation, movement
and viability are critical for pattern formation in all de-
veloping tissues, and in all species. But how could this
work? The answer requires understanding of the impor-
tance of cell and tissue micromechanics for control of
cellular biochemistry.
1.1 Mechanochemical control hypothesis
The working hypothesis that has driven our work for
more than twenty years is that although tissue mor-
phogenesis is genetically-determined and chemically-
mediated, the actual process of tissue construction
may be regulated mechanically [Ingber and Jamieson
(1982,1985); Huang and Ingber (1999)]. This idea was
based on early observations of developing epithelium
[Bernfield and Banerjee (1978)] and capillaries [Aus-
prunk and Folkman (1977)] which showed that tissue
expansion is initiated by a local increase in turnover of
the basement membrane directly beneath the subset of
cells that will subsequently form the new bud or branch
(Fig. 1). Basement membrane is a specialized extracellu-
another, and why wounds must be sutured. This is also
why whole tissues and organs exhibit residual strains, as
demonstrated by Professor Fung [Fung and Liu (1989);
Omens and Fung (1990)].
Figure 1 : Mechanical control of tissue patterning. 1)
Diagram of a small region of embryonic epithelium (E),
mesenchyme (M) and intervening basement membrane
(BM). 2) Localized secretion of proteolytic enzymes in-
creases the degradation and compliance of the BM lo-
cally. 3) Increased BM flexibility results in BM exten-
sion due to residual stresses. 4) Cell distortion supports
local growth, BM deposition and bud formation.
If the tissue is mechanically tensed, then a thinned region
Even alterations in vasculature development due to altered ECM architecture around blood
vessels leads to Metastasis
20. Acupuncture,massage to set right
a lower back pain,application of
‘Traction forces’ to reset the
displaced muscle and bone
configurations are common
clinical practices
Breast impant surgeries are
becoming so common
nowadays…Would be exciting to
realise how the surrounding tissue
adjusts to allow an external entity to
create space for itself in such a
compact,uniformly structured
21. Mutation or deletion of the polycystin genes that encode mechanosensitive ion channels
that mediate urine flow sensation in kidney epithelium leads to the development of
Polycystic kidney disease
Acute Cell contractility is a common feature of many diseases Botulinum A (Botox) D is
being tested as a treatment for a wide range of ailments,including stroke paralysis,
(Nauli M. Saurya et al. 2006)
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(2005)Acta Biomaterialia 1, 281–29
• Jorge Alegre-Cebollada,Raul Perez-Jimenez, Pallav Kosuri and Julio M. Fernandez. Single-
molecule Force Spectroscopy Approach to Enzyme Catalysis,J Biol Chem. 2010 June 18;
285(25): 18961–18966
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• Surya M. Nauli, Sandro Rossetti, Robert J. Kolb, Francis J. Alenghat, Mark B. Consugar, Peter C. Harris†
et al. Loss of Polycystin-1 in Human Cyst-Lining Epithelia Leads to Ciliary Dysfunction, Journal of the
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• Molecular Mechanochemistry: An Emerging Discipline At The Nexus Of Biology And Physics, Back to
Eurek Alert, Public release date: 18-Feb-1998
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and nutrition affect pre-mRNA splicing of a muscle gene associated with performance, energetics and
life history, J Exp Biol. 2008 Dec;211(Pt 23):3653-60.
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Involvement of G proteins in mechanochemical signal transduction, Circ Res 1996 Oct;79(4):834-9
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