This document discusses different types of receptors and provides examples. It covers four main types of receptors:
1. G protein-coupled receptors such as those for epinephrine and serotonin.
2. Ion channel receptors such as the acetylcholine receptor.
3. Tyrosine kinase-linked receptors such as cytokine receptors.
4. Receptors with intrinsic enzymatic activity, also called receptor tyrosine kinases, which have their own catalytic domain like growth factor receptors. Examples of these include guanylate cyclase, serine-threonine kinases, receptor tyrosine phosphatases, and RTKs.
Basic Mutagenic signal Transduction or the cancer signal transduction that control cell cycle are important pathways to understand cancer in molecular level and to invent targeted treatment.
The biology of neuroendocrine tumors remains poorly understood. Thanks to the United Kingdom & Ireland Neuro-Endocrine Tumor Society for inviting me to overview current knowledges during its yearly meeting. Enclosed, please find attached the slides that were used for this lecture. I hope this will generate insights for pushing forward the discovery of novel targets and biomarkers.
Basic Mutagenic signal Transduction or the cancer signal transduction that control cell cycle are important pathways to understand cancer in molecular level and to invent targeted treatment.
The biology of neuroendocrine tumors remains poorly understood. Thanks to the United Kingdom & Ireland Neuro-Endocrine Tumor Society for inviting me to overview current knowledges during its yearly meeting. Enclosed, please find attached the slides that were used for this lecture. I hope this will generate insights for pushing forward the discovery of novel targets and biomarkers.
This presentation (in English) made at ONCOTRANS in Besançon on Friday 3rd 2017 reviews the potential for TGF-beta inhibition in hepatocellular carcinoma based on preclinical and clinical data.
Hallmarks of cancer and radiopharmaceuticalsAlice Viana
In this presentation I review the article Hallmarks of cancer: next generation, from Hanahan and Weinberg, and make a parallel with potential and current targets of radiopharmaceuticals for diagnosis and treatment.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
This presentation (in English) made at ONCOTRANS in Besançon on Friday 3rd 2017 reviews the potential for TGF-beta inhibition in hepatocellular carcinoma based on preclinical and clinical data.
Hallmarks of cancer and radiopharmaceuticalsAlice Viana
In this presentation I review the article Hallmarks of cancer: next generation, from Hanahan and Weinberg, and make a parallel with potential and current targets of radiopharmaceuticals for diagnosis and treatment.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
1. Classification of Receptors
1. G Protein coupled receptors
epinephrine, serotonine, glucagon
2. Ion channel receptors
acetylcholine receptor
3. Tyrosine kinase-linked receptors
cytokine-receptor family
4. Receptors with intrinsic enzymatic activity
the receptor has intrinsic catalytic activity
receptor tyrosine kinases
2. Receptors with intrinsic enzymatic activity
1. Guanylatcyclase: GTP -> cGMP
ANP: peptide hormone, atrium of the heart upon
Upon rising blood pressure – decreases vascular resistance
via a cGMP dependent kinase
2. serin-threonine kinases: TGF –ß superfamily
growth inhibition, bone formation,
3. receptor tyrosine phosphatases:
CD45, expressed on B and T lymphocytes
4. RTKs: EGFR, Insulin, VEGFR
4. Receptors with intrinsic enzymatic activity
1. Guanylatcyclase: GTP -> cGMP
ANP: peptide hormone, atrium of the heart upon
rising blood pressure – decreases vascular resistance
via a cGMP dependent kinase
2. serin-threonine kinases: TGF –ß superfamily
growth inhibition, bone formation,
3. receptor tyrosine phosphatases:
CD45, expressed on B and T lymphocytes
4. RTKs: EGFR, Insulin, VEGFR
5. cell type specific
glykosylation
B220 B cell specific
CD45 exists in various isoforms
D1: active phosphatase
highly conserved
D2: inactive
required for
correct folding
6.
7. Constitutive activation of CD45 leads to
lymphoproliferation and autoimmunity in mice
Cell 2000, 103: 1059
8. Inactivation of CD45 leads to Severe
combined Immuno Deficiency (SCID)
Nature Med 2000, 6:343
The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions
to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So
far, there have been no reports to our knowledge of a human deficiency in a tyrosine-
specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a
large deletion at one allele and a point mutation at the other. The point mutation resulted
in the alteration of intervening sequence 13 donor splice site. The patient presented at 2
months of age with severe combined immunodeficiency disease. The population of
peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen
stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels
decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte
dysfunction.
9. Implications for Medicine
Inhibitors of CD45 have implications in transplant medicine –
prevention of kidney rejection in mouse models has been proven
microglial activation by ß-amyloid peptide can be prevented –
Alzheimers disease
the various specific activatio forms may allow for a relatively specific
inhibition dependent on the indication
10. RTKs
NGF, PDGF, FGF, EGF, Insulin
regulate cell survival, proliferation, differentiation
therefore found in cancer
constitutive active RTKs
RTKs-ras as important signalling
cascade leading to cancer
11. ligand binds a dimer –
dimerization of the receptor –
activation of its kinase activity –
tyrosine phosphorylation of its own
cytosolic domaine
25. VEGF
•VEGF is a homodimeric glycoprotein,
binding to VEGF-Receptors on
vaskular endothelial cells
•Molecular weight: 45,000Da
•VEGF plays a key role for the
formation of blood vessels
(Angiogenesis)
Ferrara N, et al. Endocr Rev 1997;18:4–25
VEGF = vascular endothelial growth factor
26. Die VEGF Familie und ihre Rezeptoren
Adapted from Ferrara N. Nat Med 2003;9:669–76
Migration, proliferation, permeability, DNA synthesis, survival
Lymphangiogenesis
Angiogenesis
– P
P–
– P
P–
VEGF-A
VEGF-B
PlGF
VEGFR-1
VEGF-A
VEGFR-2
VEGF-C
VEGF-D
VEGFR-3
P–
P–
P–
P–
– P
– P
– P
– P
27. Angiogenesis contributes to Tumorigenesis,
tumor growth and Metastasis
Modifiziert nach Poon RT-P, et al. J Clin Oncol 2001;19:1207–25
Schritte, bei denen Angiogenese eine Rolle bei der Tumorprogression spielt
Prämalignes
Stadium
Maligner
Tumor
Tumor-
Wachstum
Gefäß-
invasion
ruhende
Mikrometastase
Offene
Metastasierung
(Avaskulärer
Tumor)
(Angiogenic
switch)
(Vaskularisierter
Tumor)
(Tumorzell-
freisetzung)
(Streuung in
entfernte Organe)
(Zweite
Angiogenese)
28. The “angiogene switch”
and Tumordevelopment
Modifiziert nach Bergers G, et al. Nat Rev Cancer 2002;3:401–10
Kleiner Tumor (1–2mm)
• avaskulär
• ruhend
größerer Tumor
• vaskularisiert
• Metastasierungspotential
Angiogenic switch
führt zur Überexpression
von pro-angiogenen Faktoren,
wie zum Beispiel VEGF
29. VEGF overexpression correlates
with a bad prognosis
Study Cancer n Tumours (%) Prognostic value
Gasparini, 1997 Breast 260 95 Relapse-free survival, overall survival
Toi, 1995 152 55 Increased vascular density and relapse-
free survival
Imoto, 1998 Lung NSCLC 91 53 Overall survival
O’Byrne, 2000 NSCLC 223 47 Tumour size, vascular density
Volm, 1997 SCLC 109 59 Overall survival
Maeda, 2000 GI CRC 100 37 Overall prognosis
Amaya, 1997 CRC 136 43 Vascular density
Ishigami, 1998 CRC 60 100 Clinical stage, metastasis
Ogata, 2003 Oesophagus 92 24 Overall survival
Shih, 2000 Oesophagus 117 31 Overall survival
Paley, 1997 Ovarian 68 43 Disease-free survival
Yamamoto, 1997 70 97 Overall survival
Jacobsen, 2004 Renal 229 100 Tumour size and stage, survival
Aguayo, 2002 Haem. AML 58 100 Survival
Verstovsek, 2002 Haem. CML 184 100 Survival
32. Classification of Receptors
1. G Protein coupled receptors
epinephrine, serotonine, glucagon
2. Ion channel receptors
acetylcholine receptor
3. Tyrosine kinase-linked receptors
cytokine-receptor family
4. Receptors with intrinsic enzymatic activity
the receptor has intrinsic catalytic activity
receptor tyrosine kinases
34. Y
Y Jak Jak P
P
P
P
IFN-α
IFN-β
IFN-γ
IL-2, -3, -4, -5,
-7, -9, -13, -15
GM-CSF, Epo,
Prl, GH, TPO
Jak1
Jak3
Jak2
Stat4
Stat5a
Stat5b
Immuno-
modulation
Stat6
Tyk2
Stat1
Stat2
Growth Inhibition
Cell cycle arrest
Apoptosis
Jak1
Proliferation
Survival
Differentiation
Cancer
Progression
Stat3
Stat5b
Stat5a
Jak1
Jak2
35. O´Shea J. et al., Ann. Rheum. Dis., 2013
Cytokine signaling and specificity
36. “An acquired mutation in JAK2 has been described in
nearly all patients with the myeloproliferative
disorder (MPD), polycythemia vera (PV), and half
those with essential thrombocythemia (ET) and
idiopathic myelofibrosis (IMF). The V617F mutation
arises in a multipotent progenitor.”
James et al. Nature. 2005;434:1144-1148
Baxter et al. Lancet.2005;365:1054-1061
Levine et al. Cancer Cell. 2005;7:387-397
Kralovics et al. N Engl J Med. 2005;352:1779-1790
caJAK2 (V617F)
STAT5
STAT5
Hyperactive tyrosine kinase signaling
37. The pseudokinase
is a Serine/Threonine kinase
Ungureanu D. et al., and
Bandaranayake RM et al., Nat.
Struc. Mol. Biol., 2011 and 2012
The JAK2 kinase
38. The correct response of the target cell to cytokines
duration of response
normal response
C
magnitude
of response
signal new signal
too strong
too long
too weak
too short
C
C
C
C
C
C
excessive
production
of
mediators
target cell
C
C C
C
too many
receptors
C
C C
C
inefficient shut-
down
of the signal
cascade
mediator-
independent
activation
(mutations)
overshooting response of the target cell possible disease development
C
39. STATs have a unique C-terminal transactivation domain
40. Very similar DNA binding between STATs, but tissue specific
transcriptional regulators
Kang et al., BMC Genomics, 2013
Genome-wide STAT binding validated the cytokine-dependent nature of STAT binding to DNA.
STAT binding is primarily defined by the cell type and less so by the individual STAT protein.
The number of binding sites greatly varied between different cell contexts.
The total number of STAT enriched binding sites ranged from several hundred to one hundred thousand
Overlap of common binding sites between STATs 3 and 5 in T cells exceeds binding between STAT5 in T cells
and non-T cells.
44. Mimic of cytokine signaling through STAT5 gain of function
magnitude
of respone
too strong
too long
signal
Onishi et al., MCB, 1998
Moriggl et al., Cancer Cell, 2005
Harir et al., Blood, 2007
Li et al., Leukemia, 2007
Harir et al., Blood, 2008
Grebien et al., Blood, 2008
Baumgartner et al., Amer. J. Patho., 2010
Li et al., Blood, 2010
Li et al., Leukemia, 2010
Friedbichler et al., Blood, 2010
S710->F
Y 793
1 136
domain
DNA binding SH2
693 725 779
S S
transactivation
/pY-stability
cS5a
duration of response
normal
STAT5a oligomerisation
domain
786
Y
699 730
S
linker
domain
S715->F
687
N642->H Y665->F
Gain of function of STAT5b in Large Granular
Lymphocytic Leukemia patients
Rajala HL et al., Blood, 2013
1 136
domain
DNA binding SH2
transactivation
/pY-stability
cS5b
STAT5b oligomerisation
domain
linker
domain
687
45. Palmer DC and Restifo NP,
Trends Immunology, 2009
Hypermethylation or genetic deletion of
SOCS family members in cancer