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Receptores Catalíticos
Paula Campello-Costa
RECEPTORES CATALÍTICOS OU ENZIMÁTICOS
CARACTERÍSTICAS COMUNS DOS RECEPTORES CATALÍTICOS
3. Receptores tipo tirosina fosfatase Removem grupos fosfato dos resíduos tirosina de
proteínas de sinalização intracelular específicas. Ex:
CD45, interações cel-cel
4. Receptores serina-treonina cinases Fosforilam resíduos serina ou treonina específicos em
proteínas regulatórias de genes. Ex: TGFβ, BMPs.
6. Receptores associados a histidino cinases Ativam uma via de sinalização de “dois componentes”
onde a cinase auto-fosforila a sua histidina e transfere
imediatamente o fosfato para segunda proteína de
sinalização celular. Ex: bactérias (quimiotaxia).
CLASSIFICAÇÃO DOS RECEPTORES CATALÍTICOS
3. Receptores tipo tirosina fosfatase Removem grupos fosfato dos resíduos tirosina de
proteínas de sinalização intracelular específicas. Ex:
CD45, interações cel-cel
4. Receptores serina-treonina cinases Fosforilam resíduos serina ou treonina específicos em
proteínas regulatórias de genes. Ex: TGFβ, BMPs.
6. Receptores associados a histidino cinases Ativam uma via de sinalização de “dois componentes”
onde a cinase auto-fosforila a sua histidina e transfere
imediatamente o fosfato para segunda proteína de
sinalização celular. Ex: bactérias (quimiotaxia).
RECEPTORES TIROSINA CINASES
dical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
1. Introduction study, which revealed that diabetes increases the risk of
dementia [6,7]. Subsequent clinical and epidemiologic
Understanding the molecular basis of neuronal dysfunc-
studies have confirmed this association (reviewed in [8])
tion and memory loss in Alzheimer’s disease (AD) has
and demonstrated that impaired metabolic parameters,
ng preclinical and clinical evidence supports a pathophysiological connection between
become a major research and public health challenge
such as hyperglycemia and hyperinsulinemia, correlated
because the number of cases is predicted to increase expo-
positively with development of AD-related pathology in hu-
disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are
nentially during the next few decades, and effective treat-
mans [9–11]. Moreover, AD brains exhibit defective insulin
ments capable of halting disease progression are still
NGF INDUZ A ATIVAÇÃO
DE DIFERENTES VIAS DE
SINALIZAÇÃO CELULAR
Removem grupos fosfato dos resíduos tirosina de proteínas de sinalização intracelular específicas.
Ex: CD45, interações cel-cel
RECEPTORES SERINA-TREONINA CINASES
Fosforilam resíduos serina ou treonina específicos em proteínas regulatórias de genes.
Ex: TGFβ, BMPs.
Indução Neural
1
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678;
2
DOI: 10.3892/ijo.2015.2816
Role of TGF in regulation of the tum
Abstract. Deregulation of cell signaling homeostasis is
a predominant feature of cancer initiation and progres-
microenvironment and drug delivery (Re
7. Therapeutic applications of TGF targeting
8. Conclusions and future perspectives
sion. Transforming growth factor (TGF ) is a pleiotropic
cytokine, which regulates numerous biological processes 1,2
of various tissues in an autocrine and paracrine manner. 1. Introduction and
Aberrant activity of TGF signaling is well known to play
dual roles in cancer, depending on tumor stage and cellular The crucial role of transforming growth factor (TGF ) in
context. The crucial roles of TGF in modulating the tumor tumor progression, metastasis and treatment has been well
microenvironment, its contribution to the accumulation1of
mechanical forces within the solid constituents of a tumor
recognized and has become the topic of extensive research.
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, Univ
Among the effects, TGF can regulate cancer cell proliferation,
and its effects on the effective delivery of drugs are also 2
contribute to epithelial-to-mesenchymal transition (EMT),
becoming increasingly clear. In this review, we discuss the suppress the function of immune cells compromising immune
latest advances in the efforts to unravel the effects of TGF -
signaling in various components of the tumor microenviron- blasts and cause overproduction of extracellular matrix (ECM)
in the tumor. While it has been known for over two decades
the efficacy of drugs. We also report the implications of that anti-cancer drugs cannot penetrate deep into collagen-rich
tumor mechanics in cancer therapy and the potential usage
of anti-TGF agents to enhance drug delivery and augment
recently TGF
pathway thus, increase intratumoral drug concentration and treatment
to enhance personalized tumor treatment. DOI: 10.3892/ijo.2015.2816
present a brief description of TGF synthesis and activation
Contents along with its signaling pathways. Following, we discuss the
effects of TGF on tumor progression, its pathway alterations
1. Introduction Abstract. Deregulation of cell signaling homeostasis is
in cancer as well as its effects on EMT, immune cells function, 7. Therapeutic applications of
2. TGF synthesis and activation
3. TGF signaling pathways a predominant feature
the above, we review the barriers of delivery
to the effective cancer of initiation and progres- 8. Conclusions and future pers
4. TGF signaling in cancer initiation and tumor progression drugs caused by TGF and how regulation of TGF signaling
5. The effects of TGF on the tumor microenvironment sion.can Transforming growth
be employed to optimize delivery factor
of therapeutic agents (TGF ) is a pleiotropic
6. TGF , tumor desmoplasia and barriers to drug delivery and overall survival (1-3).
cytokine, which regulates numerous biological processes
2. TGF synthesis and activation
of various tissues in an autocrine and paracrine manner. 1. Introduction
The TGF superfamily encompasses around 40 secreted cyto-
Correspondence to: Aberrant
Biophysics Laboratory, Department of Mechanical and Manufacturing
activity
kines, including TGF of TGF signaling is well known to play
activins, nodal, lefty, myostatin, anti-Müllerian hormone
dual(AMH)
Engineering, University of Cyprus, Kallipoleos 75, Nicosia 1678,
Cyprus roles in cancer,
and growth differentiationdepending
factors (GDFs). Theseon tumor stage and cellular The crucial role of transformi
E-mail: tstylian@ucy.ac.cy cytokines regulate a plethora of biological functions such as
context. Theandcrucial
cell proliferation rolespatterning,
apoptosis, embryonic of TGF stem in modulating the tumor tumor progression, metastasis
Key words: cancer-associated fibroblasts, immune cells, desmoplasia, cell maintenance, cell differentiation, migration and immune
extracellular matrix, cancer therapy microenvironment, its ofcontribution
surveillance. Importantly, the effects these factors are to the accumulation of recognized and has become th
characterized as cell-type specific as well as context
mechanical forces
dependent (1-3). The within
TGF isoforms, thecommon
with most solid constituents of a tumor Among the effects, TGF can re
and its effects on the effective delivery of drugs are also contribute to epithelial-to-me
becoming increasingly clear. In this review, we discuss the suppress the function of immun
Synaptogenesis Astrocyte-induced Synaptogenesis Is Mediated by
Transforming Growth Factor ! Signaling through Modulation
of D-Serine Levels in Cerebral Cortex Neurons*
Neurobiology:
Astrocyte-induced Synaptogenesis IsReceived for publication, May 11, 2012, and in revised form, October 9, 2012 Published, JBC Papers in Press, October 10, 2012, DOI 10.1074/jbc.M112.380824
Mediated by Transforming Growth Factor ‡ ‡1 ‡1 ‡ ‡
β Signaling through Modulation of d-Serine Luan Pereira Diniz , Juliana Carvalho Almeida , Vanessa Tortelli , Charles Vargas Lopes , Pedro Setti-Perdigão , TGF-!1 and Synaptogenesis
Levels in Cerebral Cortex Neurons ‡ ‡ ‡ ‡ §
Joice Stipursky , Suzana Assad Kahn , Luciana Ferreira Romão , Joari de Miranda , Soniza Vieira Alves-Leon ,
astrocyte cultures express typical markers. Adult primary astrocytes were isolated from human temporal lobe tissue derived from
ubmitted to surgical
Pereira procedures. A magnetic
Carvalho resonance image shows the brain region used for§astrocyte isolation (A). The arrow‡represents ‡ ‡2
Luan
tical area
Almeida,
Diniz, Juliana
of the temporal lobe, from
Vanessa Tortelli, whereVargas
Charles Jorge Marcondes de Souza , Newton G. Castro , Rogério Panizzutti , and Flávia Carvalho Alcantara Gomes
tissue was obtained for astrocyte cultures. TheFIGURE 3. Levels
arrowhead of TGF-
shows the !1 secreted
atrophied hippocampal by astrocytes and TGF!RII distribution in cerebral cortex neurons. Levels of TGF-!1 present
epileptic disorder.
Lopes, PedroHuman astrocytesJoice
Setti-Perdigão, wereStipursky,
grown in DMEM/F-12 ‡ supplemented with 10% astrocyte
FCS, and (ACM) conditioned
the distribution media
of§typical were measured by ELISAs (A). Astrocytes secrete higher amounts of TGF-!1 than neurons in vitro
astrocytic
zed by immunocytochemistry.
Suzana Assad Kahn, Luciana HumanFerreira From
astrocytes express
Romão, the Instituto
the typical astrocytede Ciências
marker GFAP (B),Biomédicas
glutamate-aspartate
neurons cultured for and Hospital
transporter
12 days Universitário
TGF!RII in theirClementino
in a typical
express Fraga
membranes (B–D). Filho,
Scale Universidade
bar, 20 Federal
"m. **, p % 0.0001. Errordo RioS.E.
bars, de
on pattern
Joariinde
their membranes
Miranda, Soniza(C), and the
Vieira HLA Janeiro,
in
Alves-Leon,
Jorge Marcondes de Souza, Newton G. Castro,
a spread21941-590
distribution Rio
pattern de
over Janeiro,
the monolayer RJ,
(D). Brazil
Scale bars, 50 " m.
Assembly of synapses requires proper coordination between ing human cognitive advantages, but also in designing thera-
Click here to choose from all of JBC's e-mail alerts
pre- and postsynaptic elements. Identification of cellular and peutic approaches to repair the injured human nervous system.
This article cites 73 references, 22 of which can be accessed free at
molecular events in synapseFIGURE formation 4. TGF-
and !1 maintenance
induces synaptogenesis
FIGURE 4. is a!key in cerebral cortex neuronal cultures. Cerebral cortex neurons were cultured for 12 d
http://www.jbc.org/content/287/49/41432.full.html#ref-list-1
Neurobasal medium alone orNeurobasal
TGF-
supplemented
medium alone withDespite
1 induces synaptogenesis
10 ng/mlwith
or supplemented
compelling
ng/ml!of1.
of10TGF- The
TGF-
advances
in cerebral cortex neuronal
number
!1. The number of
in
cultures. Cerebralthe
cortex identification
ofsynaptophysin/PSD-95
neurons were cultured for 12
synaptophysin/PSD-95 puncta
puncta was quantified
of cellular
days
afterwas
in the presence of
12 daysquantified
(A–C). Levels aft
step to understand human of perception,
synaptic proteinslearning, memory, by and
of synaptic proteins
were evaluated and
were evaluated
Western bymolecular
blotting Western
assaysblotting events
assays
(D). (D). Scale
Scale in
bar,bar,
20 synapse
20 "
"m.
m.**,**,
p %p %formation,
0.0001. Error bars, S.E.
0.0001. Error bars,a fundamental
S.E.
SB – inibe TGFb cognition. A key role for astrocytes in synapse formation
TGF-!1 and Synaptogenesis and question remains unresolved. Is the number of synapses an
function has been proposed. Here, we show that transforming intrinsic property of neurons, or is it controlled by extrinsic
growth factor ! (TGF-!) signaling is a novel synaptogenic path- signals or non-neuronal determinants?
way for cortical neurons induced by murine and human astro- The transforming growth factor ! (TGF-!) superfamily is
cytes. By combining gain and loss of function approaches, we constituted by multifunctional polypeptide members, which
show that TGF-!1 induces the formation of functional synapses perform critical functions in nervous system development and
in mice. Further, TGF-!1-induced synaptogenesis involves neu- repair (2–9). Disturbances in TGF-! pathways have been asso-
ronal activity and secretion of the co-agonist of the NMDA ciated with a broad spectrum of behavioral abnormalities,
te-induced synapse formation is mediated by receptor, D-serine.
TGF-! pathway. Manipulation
Cerebral cortex of D-serine
neurons were maintained signaling,
in the presence by either including cognitive impairment, affective disorders, and defi-
of DMEM/F-12
r murine (MACM) and human (HACM) astrocytegenetic conditionedor pharmacological
medium inhibition,
alone (B and D) or simultaneously withprevented
the TGF-! pathwaythe TGF-!1 cits in sensorimotor gating (10 –13). Members of the TGF-!
inhibitor,
SB; C and E). The number of synaptophysin/PSD-95 puncta was quantified after 12 days (F). Presynaptic activity for human astrocyte
um assays was evaluated by FM1-43 incubationsynaptogenic effect. Our
followed by puncta quantification (G–I).data show
Scale bars, a
20 "m. novel
*, molecular
p " 0.001; **, p "FIGURE
0.0001. mecha-
Error!1 induces ultrastructurally normal and functional synapses in vitro. Cerebral cortex neurons were cultured for 12 days in the presence of
5. TGF-
-!1 secreted by astrocytes and TGF!RII distribution in cerebral cortex neurons. Levels of TGF-!1 present in neuronal
Neurobasal medium(NCM)
superfamily
alone or and
have been stronglyassays implicated
(G–I). Arrowheads in synapse
C) and bracketsforma-
supplemented with 10 ng/ml TGF-!1. Synapse formation was evaluated by electron microscopy quantification of the number of
nism that secrete
mighthigherimpact synaptic
of TGF-!function andinemphasize theIn both cases, asymmetric synapses (presumably excitatory) structurally normal are observed. TGF-!1 increased the number of synapses,
synapses (A, C, and E) and length of PSD density (B, D, and F), and electrophysiological (A and (B and D) indicate
oned media were measured by ELISAs (A). Astrocytes amounts 1 than neurons vitro. !-Tubulin-III-positive
although their ultrastructure tion
seemed in to beinvertebrates (14 synapses.
–18) and, more0.5 "m (Arecently,
and C) and 0.2 "in m (Bvertebrates
postsynaptic density.
days express TGF!RII in their membranes (B–D). Scale bar, 20 "m. **, p % 0.0001. Error bars, S.E. indistinguishable from control Scale bars, and D). **, p % 0.0001. G–I,
ot only highlight the evolutionary aspect evolutionary
of the neurons aspect ofpresence
in the the synaptogenic
of TGF-!1 for property
12 days and ofelectrophysiological
astrocytes,
analyzed effects of TGF-!1 treatment. G, representative raw current traces illustrate differences in spontaneous activity recorded in the control (Ctrl)
roperty of astrocytes but point to TGF-! signal- synapse formation by immunocytochemistry, Western and TGF-blot-
!1-treated group. The(19 –22).of the amplitude and interval between events of the two groups were significantly different (p % 0.001; Kolm-
distributions
thus shedding light on new potential therapeutic targets for
ogorov-Smirnov syn-
test; n " 5,177 and 8,580 events, from 19 and 18 neurons, respectively) (H). Averaged voltage-activated Na current traces obtained from five
chosen neurons in eachGlial
condition cells
!
ved synaptogenic glia-induced pathway present ting, electron microscopy, and electrophysiological assays. randomly The are
illustrate the key
effect determinants
of TGF- in(I).the
!1 (p % 0.001 versus control) formation,
Error bars, S.E. stabiliza-
s and vertebrates, including humans. aptic deficit diseases.
presence of synapses in cerebral cortex cultures was first mor- tion, and elimination of synapses, in either the peripheral or
ces Synapse Formation between Cerebral Cortex phologically assessed by immunostaining for synaptophysin
cultures. There was no difference in the average length of the neurons (n " 19) showed significantly higher frequencies
ong the TGF-! family, TGF-!1 has been and PSD-95. After 3 FIGURE
days in 5.culture
TGF-!1 (data postsynaptic
not shown),
induces ultrastructurally central
the densitiesnormal
(PSD), but
and nervous
their
functional system
number increased
synapses by (CNS)
(2.5vitro.
in (23–32).
# 0.3 Cerebral
versus 0.3It
1.6 #cortex remains
s$1neurons p %unclear
in control;were0.05, Student’s
cultured fort 12
150% (Fig. 5, E and F). test) and amplitudes (130 # 14 versus 75 # 5 pA; p % 0.001,
ated in synapse formation in invertebrates (15) untreated neurons contained strikingly few sites of colocalized
Neurobasal medium alone or supplemented withwhether
10 ng/ml glia-driven
TGF- ! 1. Synapsesynaptogenesis
formation was is a
evaluated general
by principle
electron that
microscopy quantifi
To ascertain if the increase in colocalized puncta reflected Student’s t test) than control neurons (n " 18). The distribu-
RECEPTORES GUANILIL- CICLASES
MEMBRANAS
Qual o papel da fluidez de membrana nos eventos de sinalização química? Como esta fluidez é modulada nas membranas
biológicas?
Diferentes tipos de proteínas são encontrados de acordo com sua associação à membrana. Dê pelo menos um exemplo de
função para cada tipo de proteína que você descreveu.
Defina os dois principais tipos de canais iônicos que podem estar presentes nas membranas celulares.
SINALIZAÇÃO CELULAR I
3) Diferencie os seguintes tipos de sinalização quanto ao alvo e a distância percorrida pela molécula sinalizadora: parácrina,
endócrina e sináptica. Cite alguns exemplos de cada tipo.
4) Porque a mesma molécula sinalizadora (por ex. a Acetil Colina) pode ter diferentes efeitos biológicos nos seus vários
alvos. Exemplifique
7) Descreva resumidamente o mecanismo de transdução de sinal dos receptores acoplados à proteína G (metabotrópicos).
Cite as principais subunidades desta proteína.
SINALIZAÇÃO CELULAR II
Associe a natureza da molécula sinalizadora (hidrofílica ou hidrofóbica) à localização do receptor. Justifique sua resposta.
Maconheiro velho
Todo maconheiro velho reclama da qualidade da maconha atual. Perto da maconha daquele tempo, dizem, a de agora é uma
palha sem graça. A observação é paradoxal, porque a maconha de hoje tem concentrações muito mais altas de THC, o
componente psicoativo da planta, do que as contidas nos baseados de 20 anos atrás. A queixa procede, no entanto. O THC
inalado, ao chegar ao cérebro, libera quantidades suprafisiológicas de neurotransmissores - como a dopamina - associados
às sensações de prazer e de recompensa. Como tentativa de adaptação à agressão química representada pela repetição do
estímulo, os circuitos de neurônios envolvidos na resposta, sobrecarregados, perdem gradativamente a sensibilidade à
droga, produzindo concentrações cada vez mais baixas dos referidos neurotransmissores. Nessa fase, a nostalgia toma
conta do espírito do usuário. É por causa desse mecanismo de tolerância ou dessensibilização que o prazer induzido não
apenas pelo THC, mas por qualquer droga psicoativa diminui de intensidade com a administração prolongada. (...)
A divisão celular é promovida pela atividade da RAS- a via de ativação normal é feita pela
ligação da GTP. Em alguns cânceres o gene RAS sofre mutações que ativa continuamente
a proteína RAS, estimulando continuamente a divisão celular.
RECEPTORES ASSOCIADOS A TIROSINA CINASES
Associam-se a
proteínas
intracelulares que
apresentam atividade
tirosina cinase. Ex:
RECEPTORES ASSOCIADOS A HISTIDINO CINASES
Ativam uma via de sinalização de “dois componentes” onde a cinase auto-fosforila a sua histidina e
transfere imediatamente o fosfato para segunda proteína de sinalização celular.
Ex: bactérias (quimiotaxia).