Sealizacin molecular

Julio Hilario Vargas

Departamento de Fisiologa Humana
Facultad de Medicina
Universidad Nacional de Trujillo
Friend mouse leukemia virus (yellow) budding from infected T-lymphocyte (blue).
Credit: Elizabeth Fischer and Kim Hasenkrug, NIH
http://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=false
Caption: T-lymphocyte. Coloured Transmission Electron Micrograph (TEM) of a section through a T-lympho-
cyte white blood cell. D. PHILLIPS/SCIENCE PHOTO LIBRARY.
http://www.sciencephoto.com/media/305086/enlarge
This coloured transmission electron micrograph (TEM) shows a section through the cell membrane of a T-lymphocyte white blood
cell (T-cell). The "bubbles" are budding Human Immunodeficiency Viruses (HIV). Science & Technology May 22, 2009
The fluid-mosaic model of the cell membrane
2004 Nature Publishing Group Pietzsch, J. Mind the membrane. Horizon Symposia: Living
Frontier, 1-4 (2004). All rights reserved.
The diverse functions of proteins in the plasma
membrane
http://www.nature.com/scitable/topicpage/protein-function-14123348
2010 Nature Education All rights reserved.
Membrana celular
Viola A, Gupta N. Tether and trap: regulation of membrane-raft dynamics by actin-binding proteins. Nat Rev Immunol. 2007 Nov;7(11):889-96.
GPI: Glycosylphosphatidylinositol
Possible roles of membrane rafts in lymphocyte migration
Viola A, Gupta N. Tether and trap: regulation of membrane-raft dynamics by actin-binding proteins. Nat Rev Immunol. 2007 Nov;7(11):889-96.
Formas de sealizacin celular
Endocrino
Paracrino
Intracrino
Autocrino
Neuroendocrino
Feromonal
Formas de sealizacin celular
Endocrino Paracrino
Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.
Nature Reviews Immunology 5, 560-570 (July 2005)
Hormonal Therapy and Hormonal-Receptor-Positive Breast CA With
HER2: Crosstalk Between ER and HER2 Pathways
E: Estrogen; ER: Estrogen receptor: HER2: human epidermal growth factor receptor
2; EGFR, ErbB-1, HER1 in humans: Epidermal growth factor receptor
Formas de sealizacin celular
Autocrino
Intracrino
Model of tolerance induction by B7-dependent signaling in DCs.
Nature Immunology 3, 1056 - 1057 (2002)
Menendez and Lupu Breast Cancer Research 2007 9:111
HRG: Growth factor heregulin
HER: Human EGFR related
Formas de sealizacin intercelular
Neuroendocrino
Neurophysiological, Neuroimmunological, and Neuroendocrine. Basis of Pruritus. Journal of
Investigative Dermatology (2006) 126, 17051718
DRG: Dorsal root ganglion
Formas de sealizacin intercelular
Feromonal
Wyatt T. Pheromones and Animal Behaviour: Communication by Smell
and Taste. Cambridge University Press. Cambridge, UK. 2003. p 18.
Tipos de receptores
De membrana
Intranucleares
http://www.motifolio.com/5111102.html
http://www.rci.rutgers.edu/~uzwiak/AnatPhys/Endocrine_System.html
Receptores nucleares
Mechanisms of DNA binding and transcriptional activation
Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nature Reviews
Immunology 6, 44-55 (January 2006)
RXR: Retinoid X receptor, HSP: Heat-shock protein, GPCR, G-protein-coupled receptor; MAPK, mitogen-activated protein
kinase; PKA, cAMP-dependent protein kinase, PPAR: Peroxisome-proliferator-activated receptors
PPAR Peroxisome-proliferator-activated receptor iNOS, inducible nitric-oxide synthase; IRF3, interferon-regulatory factor 3;
MyD88, myeloid-differentiation primary-response gene 88; NCoR, nuclear-receptor co-repressor; NF-B, nuclear factor-B;
TLR4, Toll-like receptor 4; TRIF, Toll/interleukin receptor-domain-containing adaptor protein inducing interferon- ;
UBCH5, ubiquitin-conjugating enzyme H5.
Combinatorial roles of nuclear receptors in inflammation and immunity. Christopher K. Glass &
Sumito Ogawa Nature Reviews Immunology 6, 44-55 (January 2006)
Model for how PPAR and the glucocorticoid receptor could function to integrate local
and systemic signals to counter-regulate inflammatory responses
Receptores de membrana: tipos
Receptores ligados a canales inicos
COMPONENTE CONCENTRACION
INTRACELULAR
(mM)
CONCENTRACION
EXTRACELULAR
(mM)
Cationes
Na
+
5-15 145
K
+
140 5
Mg
2+
0.5 1-2
Ca
2+
10
-4
1-2
H
+
7 10
-5
(10
-7.2
M or pH
7.2)
4 10
-5
(10
-7.4
M or pH
7.4)
Aniones
Cl
-
5-15 110
Comparacin de concentracin de iones
dentro y fuera de una clula tpica de mamfero
Tipos de canales inicos
- Canales de sodio por compuerta dependiente de voltaje
- Canales de calcio por compuerta dependiente de voltaje
- Canales de potasio:
. Canales de potasio por compuerta dependiente de voltaje
. Canales de potasio calcio activados
. Canales de potasio rectificador interno: afectados por ATP
intracelular, PIP2 y protena G sobre subunidades
. Canales de potasio con dominio de dos poros
- Canales de cloro
- Canales de hidrogeno por compuerta dependiente de voltaje
- Canales catinicos de esperma
- Canales compuerta ligando: Tambin conocidos como receptores
inotropicos. Se incluyen el receptor nicotnico para acetilcolina, receptor
inotropico con compuerta para glutamato, receptores con compuerta para
ATP y el receptor GABA A
Tipos de canales inicos
Calcium signalling in lymphocyte activation and disease. Nature Reviews Immunology, Sep2007, Vol. 7 Issue 9, p690-702
Store-operated calcium entry (SOCE) in T cells
CRAC: Calcium-release-activated calcium
Calcium signalling in lymphocyte activation and disease.Nature Reviews Immunology, Sep2007, Vol. 7 Issue 9, p690-702
CRAC: Calcium-release-activated calcium CsA : Cyclosporine A NFAT: Nuclear factor of activated T-cells
The CRAC-channel calcium-calcineurin-NFAT signaling
pathway as a target for therapeutic immune modulation
Calcium signalling in lymphocyte activation and disease. Nature Reviews Immunology, Sep2007, Vol. 7 Issue 9, p690-702
Ca2++ signaling pathways and functions in cells of the immune system
Receptores ligados a protena G
Neves S, Ram P, Iyengar R. G protein pathways. Science. 296: 1636-1639, (2002)
Incremento de transcripcin
gentica por incremento de AMPc
Signal transduction from G protein-coupled
receptors and integrins
Tybulewicz VL, Henderson RB. Rho family GTPases and their regulators in lymphocytes. Nature Reviews
Immunology. September 2009, 9, 630-644
Integrin activation and clustering during leukocyte migration
Adhesion mechanisms regulating the migration of monocytes. Nature Reviews Immunology 4, 432-444 (June 2004)
Getting to the site of inflammation: the leukocyte adhesion cascade updated.
Nature Reviews Immunology, Sep2007, Vol. 7 Issue 9, p678-689
GPCR: G-protein coupled receptors
LFA1: Lymphocyte function-associated antigen 1
GPRC-dependent LFA1 activation
Cinco vas por las cuales una clula blanco
puede desensibilizar una molcula seal
Receptores de membrana ligados a
enzimas
http://d3jonline.tripod.com/05-Cellular_Physiology/Receptors_I.htm
Siete subfamilias de receptores tirosina kinasa
Protenas kinasa
Modelos matemticos y computacionales
de sealizacin de receptores inmunes
Nature Reviews Immunology 4, 445-456
Examples of positive- and negative-feedback loops
downstream of antigen receptors on T and B cells.
Feedback regulation of lymphocyte signalling. Nature Reviews Immunology 4, 269-278 (April 2004)
G-Protein-Coupled Receptors Signaling to MAPK/Erk
http://www.cellsignal.com/reference/pathway/MAPK_G_Protein.html
Immunobiology of the TAM receptors. Nature Reviews Immunology, May2008, Vol. 8
Issue 5, p327-336
TAM receptors and their ligands
TAM Receptor
Inhibit inflammation in
dendritic cells and
macrophages, promote the
phagocytosis of apoptotic
cells and membranous
organelles, and stimulate the
maturation of natural killer
cells.
Lemke G, Rothlin CV.
Immunobiology of the TAM
receptors. Nat Rev
Immunol. 2008
May;8(5):327-36.
Cinco vas paralelas de sealizacin intracelular activadas
por receptores ligados a protena G, tirosina kinasa o ambas
Algunas protenas tirosina fosfatasa
LIGANDO DE
SENALIZACION
RECEPTORES ALGUNAS RESPUESTAS
Factor de crecimiento
epidermal (Epidermal growth
factor) (EGF)
Receptor EGF Estimula la proliferacin de varios tipos de clulas
Insulina Receptor de insulina Estimula la utilizacin de carbohidratos y sntesis de protenas
Factor de crecimiento
insulinoide
(Insulin-like growth factors)
(IGF-1 y IGF-2)
Receptor IGF-1 Estimula el crecimiento y supervivencia celular
Factor de crecimiento
nervioso (Nerve growth
factor) (NGF)
Trk A Estimula la supervivencia y crecimiento de algunas neuronas
Factor de crecimiento
derivado de plaquetas
(Platelet-derived growth
factors) (PDGF AA, BB, AB)
Receptores PDGF ( y ) Estimula la supervivencia, crecimiento y proliferacin de varios
tipos de clulas
Macrophage-colony-
stimulating (M-CSF)
Receptor del factor M-CSF Estimula la proliferacin y diferenciacin de monocitos/macrfagos
Fibroblast growth factors
(FGF-1 a FGF-24)
Receptores FGF (FGF-R1-FGF- R4,
mas mltiples isoformas de cada uno)
Estimula la proliferacin de varios tipos de clulas; inhibe la
diferenciacin de algunos precursores celulares; seales inductivas
en desarrollo
Vascular endothelial growth
factor (VEGF)
Receptor VEGF Estimula la angiogenesis
Ephrins (tipos A y B) Receptores Eph (tipos A y B) Estimula la angiogenesis; gua la migracin de clulas y axones
Protenas de sealizacin que actan va receptor tirosina kinasa
LIGANDO DE
SENALIZACION
RECEPTORES
ASOCIADOS A
JAKS
STATS
ACTIVADAS

ALGUNAS RESPUESTAS
-interfern Jak1 and Jak2 STAT1 Activa macrfagos; incrementa la expresin de
protenas del complejo mayor de
histocompatibilidad (MHC)
-interfern Tyk2 and Jak2 STAT1 y
STAT2
Incrementa la resistencia celular a infecciones
virales
Eritropoyetina Jak2 STAT5 Estimula la produccin de eritrocitos
Prolactina Jak1 and Jak2 STAT5 Estimula la produccin de leche
Hormona de
crecimiento
Jak2 STAT1 y
STAT5
Estimula el crecimiento al inducir la
produccin de IGF-1
GM-CSF Jak2 STAT5 Estimula la produccin de granulocito y
macrfagos
IL-3 Jak2 STAT5 Estimula la produccin temprana de glbulos
rojos
Algunas protenas sealizadores que actan a travs de
receptores de citoquina y la va del Jak-STAT
JAK :Janus kinases. STAT: Signal Transducers and Activators of Transcription