Copyright (c) by W. H. Freeman and Company Aula Teórica Nº 7 Sinalização inter e intra-celular.

Copyright (c) by W. H. Freeman and Company

Aula Teórica Nº 7

Sinalização inter e intra-celular


20.1 Cell-to-cell communication by extracellular signaling usually involves six steps

(1) synthesis of the signaling molecule by the signaling cell (2) release of the signaling molecule by the signaling cell (3) transport of the signal to the target cell (4) detection of the signal by a specific receptor protein (5) a change in cellular metabolism, function, or development

triggered by the receptor-signal complex (6) removal of the signal, which usually terminates the

cellular response


20.1 Signaling molecules operate over various distances in animals

Figure 20-1Receptor proteins exhibit ligand-binding and effector specificity


20.1 Hormones can be classed based on their solubility and receptor location

Water solubleLipophilic (prostaglandins)

Lipophilic • Steroids (cortisol,progesterone,estradiol,testosterone)

• Thyroxine• retinoic acid


20.1 Cell-surface receptors belong to four major classes

Figure 20-3a,b


20.1 Cell-surface receptors belong to four major classes

Figure 20-3c,d


20.1 The effects of many hormones are mediated by second messengers

Figure 20-4

• Inositol phospholipids (phosphoinositides)• Ca2+


20.1 Other conserved proteins function in signal transduction: GTPase switch proteins

Figure 20-5a


20.1 Other conserved proteins function in signal transduction: protein kinases

Figure 20-5b

• Protein Kinases• tyrosine• serine/threonine


20.1 Other conserved proteins function in signal transduction: adapter proteins

Figure 20-5c


20.1 Common signaling pathways are initiated by different receptors in a class

Figure 20-6


20.1 The synthesis, release, and degradation of hormones are regulated


20.3 G protein-coupled receptors and their effectors

Many different mammalian cell-surface receptors are coupled to a trimeric signal-transducing G protein

Ligand binding activates the receptor, which activates the G protein, which activates an effector enzyme to generate an intracellular second messenger

All G protein-coupled receptors (GPCRs) contain 7 membrane-spanning regions with their N-terminus on the exoplasmic face and C-terminus on the cytosolic face

GPCRs are involved in a range of signaling pathways, including light detection, odorant detection, and detection of certain hormones and neurotransmitters


20.3 G protein-coupled receptors

Figure 20-10


20.3 Example: G-Protein coupled -adrenergic recept. mediate the induction of cAMP synthesis

Figure 20-12


20.3 Critical features of catecholamines and their receptors have been identified

Agonistsantagonists


20.3 Model of complex formed between isoproterenol and the 2-adrenergic receptor

Figure 20-13


20.3 The structure of adenylyl cyclase

Figure 20-15


20.3 Trimeric Gs protein links -adrenergic receptors and adenylyl cyclase

animação


20.3 Some bacterial toxins irreversibly modify G proteins

Figure 20-17


20.3 Adenylyl cyclase is stimulated and inhibited by different receptor-ligand complexes

Figure 20-18


20.3 GTP-induced changes in Gs favor its dissociation from G and association with adenylyl cyclase

Figure 20-19

-subunit-subunit-subunitSwitch regions of -subunit


20.3 The structure of Gs·GTP complexed with two fragments from the adenylyl cyclase catalytic domain

Figure 20-20


20.4 Receptor tyrosine kinases and Ras

Receptor tyrosine kinases recognize soluble or membrane bound peptide/protein hormones that act as growth factors

Binding of the ligand stimulates the receptor’s tyrosine kinase activity, which subsequently stimulates a signal-transduction cascade leading to changes in cell physiology and/or patterns of gene expression

RTK pathways are involved in regulation of cell proliferation and differentiation, promotion of cell survival, and modulation of cellular metabolism

RTKs transmit a hormone signal to Ras, a GTPase switch protein that passes the signal on to downstream components


20.4 Ligand binding leads to autophosphorylation of RTKs

Figure 20-21


20.4 Ras cycles between active and inactive forms

Figure 20-22

GEF=guanine nucleotide exchange factorGAP=GTPase activating protein


20.4 An adapter protein and GEF link most activated RTKs to Ras

Figure 20-23


20.4 Analysis of eye development in Drosophila has provided insight into RTK signaling pathways

Figure 20-24

Wild-type sevenless mutant


20.4 Genetic analysis of induction of R7 photoreceptor in the Drosophila eye

Figure 20-25


20.4 Models of SH2 and SH3 domains bound to short target peptides (SH2/SH3=Src homology domain 2/3)

a) SH2 domain in GRB2 adapter protein binds to a specific phosphotyrosine in an activated RTK. The sequence surrounding the P-tyr is protein specificb) Proline rich domains in Sos(a GEF), binds to 2 SH3 domains in GRB2

(SH3 domains have similar 3D, but different a.a. sequences)

P-Tyrpocket

hydrophobicpocket

Non pro residues determine specificity


20.4 Structures of Ras·GDP-Sos complex and Ras·GTP

Figure 20-27


20.5 MAP kinase pathways

Activated Ras induces a kinase signal cascade that culminates in activation of MAP kinase

MAP kinase is a serine/threonine kinase that can translocate into the nucleus and phosphorylate many different proteins, including transcription factors that regulate gene expression


20.5 Signals pass from activated Ras to a cascade of protein kinases

Figure 20-28


20.5 Phosphorylation of a tyrosine and a threonine activates MAP kinase

Figure 20-30

Liga ATPDimerizaActivada

Ligação de MEKInduz alteração da conformação do LipExpondo a Tyr

Fosforilação da tyrE posteriormente da treonina


20.5 Multiple MAP kinase pathways are found in eukaryotic cells

Figure 20-32


20.6 Second messengers

Hormone stimulation of Gs protein-coupled receptors leads to activation of adenylyl cyclase and synthesis of the second messenger cAMP

cAMP does not function in signal pathways initiated by RTKs, but other second messengers may be initiated by both GPCRs and RTKs

cAMP and other second messengers activate specific protein kinases

cAMP specifically activates cAMP-dependent protein kinases (cAPKs)


20.6 Kinase cascades permit multienzyme regulation and amplify hormone signals

Figure 20-37


20.6 Cellular responses to cAMP vary among different cell types


20.6 Modification of a common phospholipid precursor generates several second messengers: synthesis of DAG and IP3

Figure 20-38a


20.6 Hormone-induced release of Ca2+ from the ER is mediated by IP3

Animação


20.6 IP3-induced Ca2+ increases are used to trigger various responses in different cells


20.6 Ca2+-calmodulin complex mediates many cellular responses

Figure 20-41


20.6 cGMP mediates local signaling by NO

Figure 20-42Guanilate cyclase


20.7 Interaction and regulation of signaling pathways

The effects of activation of GPCRs and RTKs is more complicated than a simple step-by-step cascade

Stimulation of either GPCRs or RTKs often leads to production of multiple second messengers, and both types of receptors promote or inhibit production of many of the same second messengers

The same cellular response may be induced by multiple signaling pathways

Interaction of different signaling pathways permits fine-tuning of cellular activities

Copyright (c) by W. H. Freeman and Company Aula Teórica Nº 7 Sinalização inter e intra-celular.

Documents

Transcript of Copyright (c) by W. H. Freeman and Company Aula Teórica Nº 7 Sinalização inter e intra-celular.