copyright (c) by w. h. freeman and company aula teórica nº 7 sinalização inter e intra-celular
TRANSCRIPT
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
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
Copyright (c) by W. H. Freeman and Company
20.1 Signaling molecules operate over various distances in animals
Figure 20-1Receptor proteins exhibit ligand-binding and effector specificity
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.1 Cell-surface receptors belong to four major classes
Figure 20-3a,b
Copyright (c) by W. H. Freeman and Company
20.1 Cell-surface receptors belong to four major classes
Figure 20-3c,d
Copyright (c) by W. H. Freeman and Company
20.1 The effects of many hormones are mediated by second messengers
Figure 20-4
• Inositol phospholipids (phosphoinositides)• Ca2+
Copyright (c) by W. H. Freeman and Company
20.1 Other conserved proteins function in signal transduction: GTPase switch proteins
Figure 20-5a
Copyright (c) by W. H. Freeman and Company
20.1 Other conserved proteins function in signal transduction: protein kinases
Figure 20-5b
• Protein Kinases• tyrosine• serine/threonine
Copyright (c) by W. H. Freeman and Company
20.1 Other conserved proteins function in signal transduction: adapter proteins
Figure 20-5c
Copyright (c) by W. H. Freeman and Company
20.1 Common signaling pathways are initiated by different receptors in a class
Figure 20-6
Copyright (c) by W. H. Freeman and Company
20.1 The synthesis, release, and degradation of hormones are regulated
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.3 G protein-coupled receptors
Figure 20-10
Copyright (c) by W. H. Freeman and Company
20.3 Example: G-Protein coupled -adrenergic recept. mediate the induction of cAMP synthesis
Figure 20-12
Copyright (c) by W. H. Freeman and Company
20.3 Critical features of catecholamines and their receptors have been identified
Agonistsantagonists
Copyright (c) by W. H. Freeman and Company
20.3 Model of complex formed between isoproterenol and the 2-adrenergic receptor
Figure 20-13
Copyright (c) by W. H. Freeman and Company
20.3 The structure of adenylyl cyclase
Figure 20-15
Copyright (c) by W. H. Freeman and Company
20.3 Trimeric Gs protein links -adrenergic receptors and adenylyl cyclase
animação
Copyright (c) by W. H. Freeman and Company
20.3 Some bacterial toxins irreversibly modify G proteins
Figure 20-17
Copyright (c) by W. H. Freeman and Company
20.3 Adenylyl cyclase is stimulated and inhibited by different receptor-ligand complexes
Figure 20-18
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.3 The structure of Gs·GTP complexed with two fragments from the adenylyl cyclase catalytic domain
Figure 20-20
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.4 Ligand binding leads to autophosphorylation of RTKs
Figure 20-21
Copyright (c) by W. H. Freeman and Company
20.4 Ras cycles between active and inactive forms
Figure 20-22
GEF=guanine nucleotide exchange factorGAP=GTPase activating protein
Copyright (c) by W. H. Freeman and Company
20.4 An adapter protein and GEF link most activated RTKs to Ras
Figure 20-23
Copyright (c) by W. H. Freeman and Company
20.4 Analysis of eye development in Drosophila has provided insight into RTK signaling pathways
Figure 20-24
Wild-type sevenless mutant
Copyright (c) by W. H. Freeman and Company
20.4 Genetic analysis of induction of R7 photoreceptor in the Drosophila eye
Figure 20-25
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.4 Structures of Ras·GDP-Sos complex and Ras·GTP
Figure 20-27
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.5 Signals pass from activated Ras to a cascade of protein kinases
Figure 20-28
Copyright (c) by W. H. Freeman and Company
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
Copyright (c) by W. H. Freeman and Company
20.5 Multiple MAP kinase pathways are found in eukaryotic cells
Figure 20-32
Copyright (c) by W. H. Freeman and Company
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)
Copyright (c) by W. H. Freeman and Company
20.6 Kinase cascades permit multienzyme regulation and amplify hormone signals
Figure 20-37
Copyright (c) by W. H. Freeman and Company
20.6 Cellular responses to cAMP vary among different cell types
Copyright (c) by W. H. Freeman and Company
20.6 Modification of a common phospholipid precursor generates several second messengers: synthesis of DAG and IP3
Figure 20-38a
Copyright (c) by W. H. Freeman and Company
20.6 Hormone-induced release of Ca2+ from the ER is mediated by IP3
Animação
Copyright (c) by W. H. Freeman and Company
20.6 IP3-induced Ca2+ increases are used to trigger various responses in different cells
Copyright (c) by W. H. Freeman and Company
20.6 Ca2+-calmodulin complex mediates many cellular responses
Figure 20-41
Copyright (c) by W. H. Freeman and Company
20.6 cGMP mediates local signaling by NO
Figure 20-42Guanilate cyclase
Copyright (c) by W. H. Freeman and Company
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