Biogenic Sulfur Gases as Biosignatures on Temperate Sub-Neptune Waterworlds
RECEPTORS-Sexl-Moriggl.pdf
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
