Senalizacion 2014

8/12/2019 Senalizacion 2014

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Sealizacin molecular

Julio Hilario VargasDepartamento de Fisiologa Humana

Facultad de Medicina

Universidad Nacional de Trujillo


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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
http://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=falsehttp://www.nsf.gov/news/news_summ.jsp?org=NSF&cntn_id=123040&preview=false


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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


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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 & TechnologyMay 22, 2009


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The fluid-mosaic model of the cell membrane

2004 Nature Publishing GroupPietzsch, J. Mind the membrane. Horizon Symposia: Living

Frontier,1-4 (2004). All rights reserved.
http://www.nature.com/http://www.nature.com/


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The diverse functions of proteins in the plasma

membrane

http://www.nature.com/scitable/topicpage/protein-function-14123348

2010 Nature EducationAll rights reserved.
http://www.nature.com/scitable/topicpage/protein-function-14123348http://www.nature.com/scitablehttp://www.nature.com/scitablehttp://www.nature.com/scitable/topicpage/protein-function-14123348http://www.nature.com/scitable/topicpage/protein-function-14123348http://www.nature.com/scitable/topicpage/protein-function-14123348http://www.nature.com/scitable/topicpage/protein-function-14123348http://www.nature.com/scitable/topicpage/protein-function-14123348


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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


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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.


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Formas de sealizacin celular

Endocrino

Paracrino

IntracrinoAutocrino

Neuroendocrino

Feromonal


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Endocrino Paracrino

Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.

Nature Reviews Imm unolo gy 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


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AutocrinoIntracrino

Model of tolerance induction by B7-dependent signaling in DCs.

Nature Immuno logy 3, 1056 - 1057 (2002)

Menendez and Lupu Breast Cancer Research2007 9:111

HRG: Growth factor heregulinHER: Human EGFR related
http://breast-cancer-research.com/content/9/5/111/figure/F3


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Formas de sealizacin intercelular

Neuroendocrino

Neurophysiological, Neuroimmunological, and Neuroendocrine. Basis of Pruritus. Journal of

Investigative Dermatology(2006) 126, 17051718

DRG: Dorsal root ganglion


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Formas de sealizacin intercelular

Feromonal

Wyatt T. Pheromones and Animal Behaviour: Communication by Smell

and Taste. Cambridge University Press. Cambridge, UK. 2003. p 18.


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Tipos de receptores

De membrana

Intranucleares

http://www.motifolio.com/5111102.html

http://www.rci.rutgers.edu/~uzwiak/AnatPhys/Endocrine_System.html
http://www.motifolio.com/5111102.htmlhttp://www.rci.rutgers.edu/~uzwiak/AnatPhys/Endocrine_System.htmlhttp://www.rci.rutgers.edu/~uzwiak/AnatPhys/Endocrine_System.htmlhttp://www.motifolio.com/5111102.html


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Receptores nucleares


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Mechanisms of DNA binding and transcriptional activation

Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nature ReviewsImmunology 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


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PPAR Peroxisome-proliferator-activated receptoriNOS, 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 Immuno logy 6, 44-55(January 2006)

Model for how PPARand the glucocorticoid receptor could function to integrate local

and systemic signals to counter-regulate inflammatory responses


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Receptores de membrana: tipos


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Receptores ligados a canales inicos


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COMPONENTE CONCENTRACION

INTRACELULAR

(mM)

CONCENTRACION

EXTRACELULAR

(mM)

Cationes

Na+ 5-15 145

K+ 140 5

Mg2+ 0.5 1-2

Ca2+ 10-4 1-2

H+ 7 10-5(10-7.2M or pH7.2)

4 10-5(10-7.4 M or pH7.4)

Aniones

Cl- 5-15 110

Comparacin de concentracin de iones

dentro y fuera de una clula tpica de mamfero


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Tipos de canales inicos


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- 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 ATPintracelular, 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


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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


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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


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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


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Receptores ligados a protena G


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Neves S, Ram P, Iyengar R. G protein pathways. Science. 296: 1636-1639, (2002)


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Incremento de transcripcin

gentica por incremento deAMPc


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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


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Integrin activation and clustering during leukocyte migration

Adhesion mechanisms regulating the migration of monocytes. Nature Reviews Immunology 4, 432-444 (June 2004)


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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


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Cinco vas por las cuales una clula blanco

puede desensibilizar una molcula seal

R t d b li d


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Receptores de membrana ligados a

enzimas

http://d3jonline.tripod.com/05-Cellular_Physiology/Receptors_I.htm


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Siete subfamilias de receptores tirosina kinasa


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Protenas kinasa


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Modelos matemticos y computacionales

de sealizacin de receptores inmunes

Nature Reviews Immuno logy 4, 445-456


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Examples of positive- and negative-feedback loops

downstream of antigen receptors on T and B cells.

Feedback regulation of lymphocyte signalling. Nature Reviews Immunolog y 4, 269-278 (April 2004)


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G-Protein-Coupled Receptors Signaling to MAPK/Erk

http://www.cellsignal.com/reference/pathway/MAPK_G_Protein.html

TAM receptors and their ligands


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Immunobiology of the TAM receptors. Nature Reviews Immunology, May2008, Vol. 8Issue 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.


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Cinco vas paralelas de sealizacin intracelular activadas

por receptores ligados a protena G, tirosina kinasa o ambas

Al t ti i f f t


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Algunas protenas tirosina fosfatasa

P d li i i i ki


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LIGANDO DE

SENALIZACION

RECEPTORES ALGUNAS RESPUESTAS

Factor de crecimiento

epidermal (Epidermal growthfactor)(EGF)

Receptor EGF Estimula la proliferacin de varios tipos de clulas

Insulina Receptor de insulina Estimula la utilizacin de carbohidratos y sntesis de protenas


insulinoide

(Insulin-like growth factors)

(IGF-1 y IGF-2)

Receptor IGF-1 Estimula el crecimiento y supervivencia celular

Factor de crecimientonervioso (Nerve growth

factor)(NGF)

Trk A Estimula la supervivencia y crecimiento de algunas neuronas


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

Algunas protenas sealizadores que actan a travs de


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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

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