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Chapter15notes complete


Signaling Systems
Cells Often Communicate Using Extracellular __________________
These Can be Produced by a Cell and Bind to a Receptor on the Same Cell (a: _________
signaling)

Be Produced by a Cell and Bind to Another Cell Nearby (b: ___________________)

Or Hormones Produced by Cells that Travel Around the Body in the Bloodstream Before
Binding to Target Cells (c: __________________)

The Extracellular Signal Molecule (_________) Produced is the First Messenger (1)
This Binds to ____________ on or in the Target Cell (2) The Binding of a Ligand Causes a ____________________ in the Receptor, that Activates its Cytoplasmic Domain (3)
Depending on the Type of Receptor Activation can Transmit a Signal to an (Effector)
Enzyme that Produces __________________ Molecules (4/5)
________________ are Small Molecules that Activate or Inactivate Specific Proteins Second Messengers May Diffuse Through the _______________________________ Alternatively the Receptor May Act as a Recruiting Center for ____________________________________ (4a) The Proteins Interact at Specific Interaction Domains Such as ________________
In Either Scheme the Signal is Passed on Via Activation/ Inhibition of Further Relay
Proteins (the __________________) (6/7)

The Relay Protein of a Signaling Pathway are Often _______________________
These ___________________________ Other Proteins The Human Genome has _________________________ Genes The Kinases Usually Phosphorylate ___________________ Amino Acids but Some Types Phosphorylate _____________ Some __________________ are Cytoplasmic Proteins Others are Membrane Proteins (Including Receptors) Each Kinase _____________________________ Target while Ignoring All Others Some Kinase/ Phosphatases Act on a Number of __________________, Others Act on Only 1 Amino Acid in 1 Protein Many Protein Substrates are __________________________________ However Others Protein Substrates Include Ion Channels, _____________________ or Regulatory Proteins At least 50% of Proteins are _________________at 1 or More Sites ___________________________ have been Used to Screen for Different Phosphorylated Proteins in Cells For Example, the Image Shows Differences in _____________________ Present in Proteins from Different Breast Cancer Cell Lines Also a Study of 9 Different Mouse Tissues Found ______________________ Phosphorylated at 36000 Sites The Challenge is to Understand the Role of these and Other ____________________________________ The End Result (Final Step) of a Signaling Pathway can be ___________________ This Includes Changes… 1) in Gene Expression 2) in Metabolic Enzyme Activity 3) in Cytoskeletal Networks 4) in Cell Shape or Locomotion 5) in Ion Permeability 6) in DNA Synthesis 7) Leading to Cell Death (Apoptosis)
Overall, the Relaying of an Extracellular Signal to Produce a Change Inside a Cell, is
Called _____________________
There are a Large Variety of _____________________ and these Include:- 1) _______________________ (Glutamate, Glycine, NMDA, Acetylcholine, Epinephrine, Norepinephrine, Dopamine, GABA, Histamine, Serotonin, Melatonin, and Thyroid Hormone), these are Neurotransmitters or Hormones 2) _________, Nitric Oxide (NO; Vasodilation etc) and Carbon Monoxide (CO; Binds to K+ Channels) 3) _________________ (Cholesterol Derivatives:- Estrogen, Progesterone, Testosterone, Hydrocortisone, Aldosterone), Regulate Sexual Differentiation, Metabolism and Ion Homeostasis 4) Eicosanoids (Derived from Omega-3 or -6 Fatty Acids and Arachidonic Acid:- ___________________________________________________) these Induce Sleep, Regulate Pain, Inflammation, Blood Pressure and Blood Clotting They are Produced by _______________________ Enzymes that are Inhibited by NSAIDs such as Aspirin (Bayer), Ibuprofen (Advil) and Naproxen Sodium (Aleve) 5) Numerous ___________________:- These are Excreted and Bind Receptors, are Present as Transmembrane Proteins on Interacting Cells, or Bind the Extracellular Matrix 6) Others:- Including Nucleotides Such as ______________________, the Ligand for the Cannabinoid Receptor As well as Different Kinds of Ligands there are Different Kinds of _______________, These Include:- 1) _____________________________ (GPCRs); these Receptors Activate Regulatory
GTP Binding Proteins (G Proteins) Upon Ligand Binding

2) ____________________________ (RTKs); these Dimerize on Ligand Binding and
this Activates their Tyrosine Kinase Domains which Phosphorylate the Receptors
Themselves and Other Protein Substrates

3) Ligand-Gated (or __________________________) Ion Channels; Both of these
Cause an Influx of Calcium Ions which Act as Second Messengers for Example Leading
to the Release of Neurotransmitter
4) ________________________________; these Bind (Lipophilic) Steroid Hormones in the Cytoplasm Receptor-Hormone Complexes Act as ______________________ Binding to Response Elements in the Promoters or Enhancers of a Selection of Specific Genes They Act to Increase or Decrease the ____________________ of these Specific Genes 5) Some _____________________________ Bind to Cytoplasmic Tyrosine Kinases
G protein-Coupled Receptors

G-protein Coupled Receptors (GPCRs) are ______________________ that Interact
with G-Proteins
1000’s of Different Receptor Genes have been Identified in Organisms ______________________________________ Receptor Ligands Include Hormones, Chemoattractants, Neurotransmitters, ___________________________, Photons, and Opiates The Odd Number of Membrane Spans Yields a _____________________ the Cell and a ________________________ This Creates 3 Loops on the Extracellular Part of the Receptor which Form the __________________________ There are Also 3 Cytoplasmic Loops that Form _________________________ G-Proteins Bind to the ________________________
_________________ that Prevent Further Activation of G-Proteins Compete for the
Same Site
Many Accessory Proteins Such as ___________________ Also Bind to the Receptor’s Cytoplasmic Loops GPCRs have Both a Lot of Different Ligands, but Also a Number of _________________________________ These _________________________ by the G-Proteins Activated by the Receptors We will have a Few Examples, One of Which is the Effect of _____________________ on Glycogen Breakdown
The G-Proteins Themselves are _________________ (Comprised of 3 Different
Subunits)

These are Separate From the Family of ________________ (Single Subunit) G-Proteins
that Also Exist
Both the α and γ subunits have _________________ in the Plasma Membrane The Guanine Nucleotide Binding Site (GTP/GDP) is on the ______________ Interaction with an Activated Receptor (i.e. those with Bound Ligand) Leads to Replacement of ___________________ The Binding of GTP Changes the Conformation of G _________________ for the β/γ ________________________ From the Other Subunits It is then Free to Bind ___________________
Binding of G to Effector Proteins Such as _________________ (AC), Activates them

In this Case the Enzyme (AC) Turns ATP into the Second Messenger, ________
Active G can Deactivate Itself by ______________________________ and Inorganic This Results in a Conformational Change in G that ____________________ for G G Consequently __________________ and Becomes Inactive There are _____________________ G-Proteins Based on the G Subunits and the Some GPCRs Can Interact with Different G-Proteins _________________________
_____ Family Members Couple to Adenylate Cyclase

G Family Members have G Subunits that Activate Phospholipase C (PLC
Hydrolyzes Phosphorylated Phosphotidyl Inositol into ______________ (DAG) and _____________________ (IP ) Both Di-Acyl Glycerol and IP are ___________________
G Functions by __________________________

________________ are Less Well Characterized
Leads to Excessive Cell Proliferation and The G Complex Also _______________________ as it Can Also Couple to Adenylate Cyclase, PLCβ, PI 3-Kinase and K+ Ion Channels Once a Response is Made by a Receptor, to Prevent Over Stimulation, __________________________________ Also the ___________________________ have to be Inactivated ___________________ of the Receptor Takes Place in 2 Steps Firstly the Receptor is _________________________________
The Kinase is Called ___________________________________ (GRK)
There are a Small Family of GRKs that are __________________ Kinases Phosphorylation of GPCRs then Leads to the _______________________ Arrestins are a Small Group of Proteins that _______________________ for their Binding Site on the GPCR Bound Arrestin _________________________________________ by the GPCR Desensitization is 1 of the Mechanisms that make _________________________ ______________________ Can Lead to Problems Receptor Mutations ______________________________ of Rhodopsin Receptors Lead to the Death of Photoreceptor Cells Retinal Cell Death is a Cause of Blindness in the Disease ____________________ Once Arrestin is Bound to the GPCR, it can Interact with _____________ Arrestin can Also Interact with ______________________ Interaction of Bound Arrestin with Clathrin in Clathrin-Coated Pits Can Lead to ___________________________ In Endosomes, Arrestin May Act as a __________________ For Signaling Complexes For Example, __________________ May be Activated by Arrestin-GPCRs These Signals from ______________ GPCRs (and RTKs) were Surprising However, the _________________________, are Different from those from Plasma Membrane GPCRs etc GPCRs May Also be Sent to _________________________ Degradation Temporarily ____________________________ to the Particular GPCR Ligand Alternatively GPCRs in Endosomes May be ____________________________ to the Membrane Via Recycling Endosomes The Cell then Remains Sensitive to the ligand and is said to be ____________________ As Mentioned Already, the G-proteins are Inactivated by _________________________ to GDP Inactivation is Determined by the ____________________________
Termination of the Response (to a Ligand) is Sped Up by
______________________________________’ (RGSs) proteins
RGSs __________________________________ of G α Once Bound ____________________________, G is Inactivated and Binds G There are a Number of Human Diseases that are Caused by _____________ in Either GPCRs or G-Proteins Additionally Bacteria Can Take Advantage of _________________________ Cholera Toxin Produced by Vibrio cholerae Modifies G ____________________ in Adenylate Cyclase (the Effector) Therefore ______________________________ which Causes Massive Fluid Secretion People with Cholera Die from the ________________________ _________________ Produced by Bordatella pertussis Causes Whooping Cough The Toxin _______________ Interfering with Signaling Pathways in Immune Cells This Prevents ________________________________ Against the Infection
Second Messengers
cAMP is Produced by the Enzyme _________________ Its Production and Subsequent Destruction Via _________________________ is Rapid (see Figure) It Acts as a Switch to __________________________________
One Main Function is to Activate _____________________ (PKA)
Other Second Messengers Include _____________, Phosphoinositides, Inositol triphosphate (IP ), Diacyl Glycerol and Nitric Oxide Enzymes that Generate Second Messengers from Phospholipids Include Phospholipases (Lipid Splitting), Phospholipid Kinases (Adding Phosphates), and _______________________________ (Dephosphorylation) Phospholipases (Such as PLC) _____________________ of Phospholipids PLC Breaks Off the _______________________ (Usually Inositol) as Part of the Process of Generating _________________ _______________________ are Also Added by Kinases to Produce the IP Or Other IP is Generated When the Position 4 and 5 Carbons of Phosphotidyl Inositol’s (PI) Inositol are Phosphorylated by _____________ (PI4K) and ______________ (PIP5K) Additionally Another Kinase ______________(PI3K) Can Phosphorylate the Inositol Also on the Third Carbon, Giving PI(3,4,5)P i.e. _________ PI3K Overactivity has Been Associated with _______________ _____________________ Form Binding Sites for Several _____________________ in Some Proteins
One of these Domains, the _________________ has been Found in 150 Proteins
Binding of a Protein by its PH Domain to _________________, Recruits the Protein to the Cytoplasmic Leaflet of the Plasma Membrane In this Location, the Protein can then _______________________________ Activators, Inhibitors or Substrates As an Example, PIP is Produced at the Front of the Cell __________________ Towards Not All Phosphoinositides _________________________ Following ____________________ by a G-Protein (Due to GPCR Activation) The Head Group of Phosphorylated PI can Also be Cleaved Off by PLCβ to _____________________________ is Left Behind in the Membrane DAG Recruits and Activates Effector Proteins that Bear a _________________________
One Protein that May be Activated is ___________________ (PKC)
One Role of PKC is in __________________ DAG can be Mimicked by ________________ Addition of Phorbol Esters to Cultured Cells, Makes them Lose Growth Control and Behave Temporarily as _________________ Cells Engineered to _______________________ are Permanently Malignant and Cause Tumors in Mice Addition of Phorbol Esters with Other Specific Chemicals to Skin, _________________ β ___________________ Through the Cytoplasm One Major Action is that it Binds to _________________ on the Smooth Endoplasmic Reticulum One Function of the Smooth Endoplasmic Reticulum is to _________________ The IP3 Receptor Also Functions as a __________________ Binding of IP3 to the Receptor Opens the Channel ________________________ Into the Cytoplasm Calcium is Itself a _______________________ Its Elevation in Cytoplasm ______________ Plays a Role in Contraction of Smooth Muscle, Excytosis of Secretory Granules and the Response of Liver Cells to the Hormone Vasopressin The Response of Liver Cells to Vasopressin, ______________________, is Rapid But the __________________ in the Smooth Endoplasmic Reticulum and Plasma Membrane are Also Quick to Remove the Calcium This Causes _________________________________________ that Control the Cell Response
G-Protein Specificity
G-Protein Signal Transduction Pathways are usually ____________________________ 1) There are Many Different _________________ for the Same Ligand Examples Include, __________________________for Epinephrine or 15 Receptor Types for Serotonin (5-HT) Different Isoforms have Different ______________________ and can Bind Different ________________ Different Receptor Isoforms May be Expressed in the ____________ 2) There are Also Multiple __________________ In the Human Genome there are _____________________ Isoform Genes 3) Additionally there are ___________________________ forms of Gα 4) There are Also Isoforms of the Effectors Such as the __________________________ Mentioned Earlier An Example of this Variation are the ______________________________ In Cardiac Muscle Cells, Epinephrine Activates _____________________ Receptor This Activate _____________________________, which Leads to an Increase in the Rate and Force of Contraction In Smooth Muscle Cells, Epinephrine _____________________________________, _____________________ Production, Causing Muscle Relaxation Lastly, Some Adrenergic Receptors Activate _______________________
An Example:- Control of Blood Glucose
Glucose in Body Cells is Stored in Medium-Term Storage (Fat, Long-Term; ATP and Creatine Phosphate, Short-Term) ______________, a Branched Glucose Polymer Glycogen is Produced (Mainly in the Liver but Also Muscle Cells) in Response to ___________________ that is Produced (by Pancreatic Beta Cells) to Lower Blood Glucose to a Normal Level After Meals When Blood Glucose Levels Drop Below Normal _______________________ is Produced (by Pancreatic Alpha Cells) to Raise the Level Again Glucagon Stimulates ______________________________________ Additionally the (Short-Term) __________________________ (Adrenaline) Also Causes an Increase in Blood Glucose Levels This Provides ______________ to Deal with Stressful Situations Insulin Acts Via a ___________________________ (see Later) Glucagon and Epinephrine Bind _________________ Glucagon is a __________________________ Whereas, Epinephrine is a _________________________________ Structurally Both Glucagon and Epinephrine have Little in Common but Both Stimulate ________________________ to Glucose-1-Phosphate Additionally Binding of Either to its GPCR ____________________________ Hence Two Different Ligands and GPCRs, __________________________ The 2 Receptors Differ Mainly in their ___________________________ Following Activation Both Receptors Activate the ___________________________ and Increase cAMP Levels Via Adenylate Cyclase (AC) Initially, Glucagon or Epinephrine ____________________ (1) This ___________________ which Activates AC (2) AC Can Also be Inhibited, For Example by G , Activated by GPCRs for
The cAMP Diffuses Through the Cytoplasm Where it Can Bind __________________
(PKA) (3)
Inactive PKA is a Heterotetramer with _______________________________ Subunits cAMP Binds to an ___________________________ The R Subunits Normally _______________________ cAMP Binding ____________________, Releasing and Activating the C Subunits The Target Substrates of PKA in Liver Cells are 2 Enzymes Involved ____________________________
These are ___________________ (4) and _____________________ (5)
Phosphorylation of Glycogen Synthase, _____________________ and Consequently the ______________________ from Glucose Phosphorylation of Phosphorylase Kinase, _____________________ Phosphorylase Kinase can then ____________________________________________ Activating it (6) Glycogen Phosphorylase then Stimulates the _________________________________(7) Glucose-1-Phosphate is Converted Initially to ___________________
And Finally to Glucose by ____________________________ Located in the
_______________________________
Glucose is then Released into the ________________ (8) The Phosphorylated Enzymes, Glycogen Synthase, Phosphorylase Kinase and Glycogen Phosphorylase can be ____________________________________ The Dephosphorylation _______________________ cAMP and PKA Stimulation Additionally cAMP is Broken Down to AMP _____________________________
Signal Amplification
The Binding of a Single Hormone Molecule at the Cell Surface ___________________ of G-Proteins These G-Proteins Activate an _______________ that Can Produce a ________________ Likewise cAMP Activates PKA which can ________________________________ Each Also Each Activated Glycogen Phosphorylase Can Finally Breakdown __________________________ to Glucose Phosphates At Each Step there is _________________________________ This is the ___________________ Having Many Steps to the Process So that One Molecule of Ligand Can Cause a _________________________ by the Cell Control of Glycogen Breakdown is More Complicated (than Indicated) as it Also Involves __________________________ As well as Glycogen Breakdown in Liver Cells, Something Similar Happens in _________________________ Epinephrine, Glucagon and ACTH Also Lead to ___________________________ Vasopressin can Also Act Via cAMP (as well as IP /Ca Ions) but Using a As Well as its Involvement in Glycogen Metabolism cAMP __________________________________ ____________________ can Enter the Nucleus
Here it Phosphorylates the ____________________________________ (CREB)

CREB Binds to ________________________ (CRE) in the Regulatory Regions of a
Selection of Genes
The Consensus __________________________ of CREs is TGACGTCA These are Bound by _______________________ of CREB The ___________________________ Involved in Production of Glucose from Glycolysis Intermediates have CREs
More on cAMP/ PKA
cAMP is Produced in Response to ______________________ as we have Seen It has Also Been Implicated in Processes in the Nervous System Including Learning, Memory and ________________ Chronic Use of Opiates Leads to ________________________ which are Probably Implicated in Drug Withdrawal Symptoms One Hundred _________________ have Now Been Discovered So How Does PKA _________________________________ in Response to a Particular Stimulus in a particular Cell Type? Part of the Answer is that PKA is Anchored to ______________________ AKAPs (Shown in Purple Boxes) Nearly ______________ have Been Identified They Localize PKA to a __________________ in the Cell Where PKA/ AKAPs are Located _____________________ are Also Bound Different Cells Produced _______________, Specifying the Substrates PKA Will Phosphorylate in Response to cAMP AKAPs have ________________, so a Variety of Different Proteins have Become Involved in cAMP Signaling During Evolution Another Cyclic Nucleotide, ______ is Also Involved in Cell Signaling Pathways
cGMP is Made by _____________ Enzymes
There are Membrane Receptors for Peptide Hormones Such as _________________ (ANP, BNP, CNP) and _____________ (Guanylin and Uroguanylin) that have Guanylate Cyclase Domains These Make cGMP in Response to _________________ There are Also _______________________ of Guanylate Cycalse that are Regulated by Nitric Oxide
cGMP Activates ____________________ (PKG; like PKA or PKC) that Phosphorylates
Specific Protein Substrates
There are ________________________ Guanylate Cyclase Isoforms Present in _____________Cells Retinal Cells _____________________, a GPCR that Responds to Light
Absorption of Light by Rhodopsin Activates a Heterotrimeric G-Protein Called
__________________
Transducin Activates a Coupled Effector which is a _____________________ Enzyme In the Dark, _____________________________, where it Binds to cGMP-Gated Sodium Channels, Keeping them Open Activation of cGMP Phosphodiesterase by _________________, Lowers cGMP Levels Membrane _______________________ Generating Action Potentials Along the Optic Nerve Other Types of GPCRs are Involved in Detection of ________________ but we Don’t have Time to go Through that
Receptor Protein-Tyrosine Kinases
There are Over _______________________________ in the Human Genome These Proteins are Involved in ___________________:- Growth, Division, Differentiation, Survival, Attachment to Extracellular Matrix, and Cell Migration Mutant Protein-Tyrosine Kinases that Cannot be Controlled are Associated with Unrestrained Cell Division and ____________ There are 2 Groups of Protein-Tyrosine Kinases:- there are __________________________________ (RTKs), which have a Single Transmembrane Domain There are Also _____________________________ Protein-Tyrosine Kinases (TKs) RTKs are Activated by ____________________________________, or Metabolic Regulators (i.e. Insulin) Examples of Growth Factors Include ________________________ (EGF) and Platlet-Derived Growth Factor (PDGF) TKs are _______________________ by Extracellular Signals TKs ____________________ Such as the Immune Response, Cell Adhesion and Neuronal Cell Migration RTKs ___________________________ and there are 2 Mechanisms by Which this May Occur
_________________________________ where the Ligand Can Bind Receptors in 2
Places (i.e. 2 Receptors Simultaneously)
Example Ligands are PDGF or Colony Stimulating Factor-1 (CSF-1) which _____________________________
The Second Mechanism is __________________________________
Here, Ligand Binding Induces a Conformational Change that Allows ____________________________________ Example Ligands Include __________________________________________ (TGFα)
Regardless of Mechanism, 2 Receptors Dimerizing Allows ________________________
This is Where One Receptor Phosphorylates Tyrosine Residues ____________________ and Vice Versa The Autophosphorylation Sites on ______ have 2 Functions They Can Regulate the RTKs ______________ Or ___________________ for Cytoplasmic Signaling Molecules Kinase Activity is Usually Controlled by ________________________ in the Activation Loop of Kinase Domains The ________________ Normally Obstructs the ATP Binding of the Kinase Following its Phosphorylation, the Activation Loop is Stabilized _________________________________________ This Activates the Kinase Domain, Allowing the Receptor Subunits to ______________________________ This Phosphorylation Occurs on Tyrosines ________________________________ These Sites then ________________________ for Cell Signaling Proteins Signaling Proteins are Able to Bind Because they have Domains that Bind Specifically to _____________________________
______________________ Domains (PTB) and __________________Domain 2 (SH2)
_________________ Bind Tyrosines that are Part of a Asn-Pro-X-Tyr Motif However Some PTBs Bind to ________________________ Instead SH2 Domains were Originally Identified in ___________________ They are Around 100 Amino Acids and have a Binding Pocket for _______________________________ More than _________________ Containing Proteins are Encoded by the Human Genome Binding Specificity is Determined by the ______________________ the Phosphorylated Tyrosine e.g. ___________________________________ SH2 Domain Binds to pTyr-Glu-Glu-Ile Whereas _____________ SH2 Binds to pTyr-Met-X-Met Yeast _____________________________________, Showing the Lack of Tyrosine Kinase Signaling in Lower Eukaryotes
RTK Signaling Pathways
RTK Activation Results in the Formation of Signaling Complexes where _____________________________ Bind Specific Phosphorylated Sites on the Receptor The _____________________ Include Adaptor Proteins, Docking Proteins, Transcription Factors and Enzymes 1) ______________________:- Link 2 Signaling Proteins Together
They have an SH2 Domain and 1 or More ________________________ Domains e.g. Grb2 has One SH2 Domain and _____________ for Interaction with Other Proteins SH3 Binds to __________________ Such as those Found in Sos or Gab The SH2 Domain of Grb2 Binds Phosphorylated Tyrosines of ________________ Found in RTKs This Results in ________________________ Binding to RTKs
2) ____________________:- Like IRS, Supply RTKs with Further Tyrosine
Phosphorylation Sites
They Also Contain a ______________ Domain Docking Proteins Bind to the _______________________________ of the RTK After Ligand Binding to the Receptor This Provides Extra Versatility to RTKs as What Signaling Molecules are Activated, Depends on the Docking Proteins _____________________ In the Figure We See __________________________ Binding to IRS
3) ___________________:- Such as Members of the __________ are Activated by RTKs
STATs Work in the Immune System and Contain a SH2 Domain ________________________________ STAT Phosphorylated Tyrosines Can Bind the SH2 Domains of __________________________ Once a Dimerized RTK has Phosphorylated a Tyrosine in its SH2 Binding Site, a STAT can _____________________ ____________________ are then Phosphorylated A Second Phosphorylated STAT can then Bind the First ______________ __________________ but Not Monomers then Stimulate Transcription of Specific Genes in the Nucleus
4) _____________________:- Include Protein Kinases and Phosphatases, Lipid Kinases,
Phospholipases and GTPase Activating Proteins
When these have ______________ they Bind Activated RTKs and this Directly or Indirectly Activates them Enzymes can be Activated as a Result of ____________________________, Close to Substrate Enzymes can be Activated Due to _________________________________ in their Active Sites Caused by Binding to Phosphotyrosine on the RTK Lastly Enzymes Can by Regulated _______________________________ Whatever the Activation Mechanism, Activated Proteins Initiate _________________________________ that Lead to the Overall Cell Response
Ending the Response
Signal Transduction by RTKs is Usually Terminated by __________________________ One Mechanism Controlling Internalization ________________ __________________ RTK Tyrosines Act as Binding Sites for Cbl which Posses a SH2 Domain Cbl Catalyzes the ____________________ Molecule (a Small Protein that is Covalently Linked) to the Receptor Ubiquitin Labels the Receptor for ____________________________ in Lysosomes
Ras-MAP Kinase Pathway
Ras Protein was Originally Identified as a _______________________ _______________________ have Mutant RAS Genes Ras Proteins are Part of a _________________ of More than 160 Small Monomeric G-Proteins, that Includes Ras’s (30), Rab’s (65), Rho’s (20), Rap’s (5), Arf’s (30), Rheb’s (2), RGK’s (4), Rit’s(2), Miro’s (2), Ran, and Sar1 These _______________________ are Involved the Regulation of Processes Including Cell Division, Differentiation, Gene Expression, Organization of the Cytoskeleton, Vesicle Trafficking and Nucleo-cytoplasmic Transport Ras is a GTPase that is __________________________________ of the Membrane Like Heterotrimeric G-Proteins, Ras Acts as Both a ______________________ Ras is Monomeric with ___________________, Active:- GTP Bound and Inactive:- GDP Bound Ras-GTP Binds and Activates ____________________________ Ras is Deactivated by _______________________ to GDP Mutations in RAS that Prevent GTP Hydrolysis Lead to _________________ in Humans Due to its Role in Cell Proliferation Cycling of Monomeric G-Proteins Between Active and Inactive Involves Various _______________________ Including:-
1) ______________________________ (GAPs) that Accelerate GTP hydrolysis
GAPs Consequently Significantly _____________________ of a G-Protein Mediated Cell Response Mutations in 1 Ras-GAP Genes (NF1) Causes __________________, i.e. Benign Tumors Along Nerve Sheaths
2) ____________________________________ (GEFs)
GEFs Bind Inactive G-Proteins _____________________ This Leads to the Rapid Binding of __________________________
3) ______________________________________ (GDIs)
GDIs __________________________ from G-Proteins This Leads to the G-Proteins Being ______________________________
Ras-GTP Interacts with Several Downstream Targets Including the
____________________________________
The Ras-MAP Kinase Pathway is Activated when a Growth Factor Such as _________________________ Binds to its RTK Many of these RTKs then have Phosphorylated Tyrosines that Bind ________________ Protein Grb2 Binds __________________ Specific for Ras The Binding of GRB2-Sos to the RTK Locates this at the Membrane in ______________ __________________ (Due to Ras Binding GTP) Located on the Cytoplasmic Surface of the Membrane
Ras Activation Creates ___________ for a Number of Proteins Including _____ (Also
Known as ________________)
Raf is then Recruited to the membrane where it is Activated due to its ______________________________________
One of Raf’s Substrates is the ___________________ (Also Known as ____________)
_________________ by Phosphorylation by Raf
Activated MEK then Phosphorylates 2 MAP Kinase (__________) Substrates,
_______________________
ERK’s can ____________________________ Including Receptors, Cytoskeletal Proteins, Transcription Factors, Apoptosis Regulators, Kinases, and Other Signaling Proteins Once Activated _________________ Can Move to the Nucleus In the Nucleus it Phosphorylates and Activates Transcription Factors and ___________________________ These Include the Transcription Factors and Oncogenes, _______________ Many of the Genes Activated are Involved in Cell Proliferation, Including Cell Division ______________ One Gene Activated is ___________________ (________) that Dephosphorylates _______________________ Evolution has Adapted the Pathway for Many ____________________ In Yeast the MAP Kinase Casade is Used for the Response to __________________ In Fruit Flies it is Used for the Differentiation of __________________________ Flowering Plants Use it to Initiate a __________________________ In Each Organism the Core Kinases are the Same ____________________________ 14 MAPKKKs, 7 MAPKKs and 13 Different MAPKs have Been Identified __________ This Allows a Number of __________________________ to Respond to Different ______________________ e.g. Instead of Cell Proliferation, _______________________ Signals are Transmitted Along a Different MAP Kinase Pathway In this Case the Cell _____________________________ This Gives the Cell time to _________________ The _______________________ Comes from the Fact that Some MAPKKKs Phosphorylate ______________________ And Some MAPKKs Phosphorylate _________________ However Many of these Kinases are Part of _____________________ The Specificity of MAP Kinase Pathways is Also Due to Spatial Localization of Components
Spatial Localization is Achieved Using Structural Proteins Called Scaffolding Proteins
AKAPs are Examples of Scaffolding Proteins Involved in cAMP Pathways A Few Scaffolding Proteins have Enzymatic Activity as Shown by yeast Pbs2 which has MAPKK Activity Scaffolding Proteins May Prevent Proteins from Taking Part in Other Signal Transduction Pathways As a Result Several Pathways Can Share the Same Signaling Proteins Without Affecting Specificity An Example is yeast MEPKKK, Ste11 Takes Part in Both Mating and Osmoregulatory Responses Depending on Which Scaffolding Protein its Attached to When a Chimeric Ste5/Pbs2 Scaffold Protein was Produced with MAPK Hog1 Attached, Mating Factor Stimulated an Osmoregulatory Instead of a Mating Response
Calcium Ions
___________ Play a Role in Muscle Contraction, Cell Division, Secretion, Synaptic Neurotransmitter Release, Metabolism, Transcription, Cell Motility, and Cell Death This is Due to Extracellular Signals Causing an ____________________ Calcium Ions Cytoplasmic Calcium Levels are ___________________ by Calcium Ion Pumps, Exchangers, and Channels Located in Plasma and Organelle Membranes Calcium Levels in Extracellular Fluid, the ER or Plant Vacuoles are ______________ Abnormally High Cytoplasmic Calcium Levels, as in Brain Cells After a Stroke, Can Lead to ________________ As Mentioned Earlier GPCRs Can Activate Phospholipase C-β Which Splits PIP into IP3 Opens ______________________ Membrane Leading to a Rise in Cytosolic Calcium RTKs can Also Trigger a Similar Response Via __________________ which has a SH2 Domain to Bind Activated RTKs There are a Number of PLC Isoforms; _______________ is Activated by Calcium Ions; ___________________ is Activated by Ras-GTP All PLC Isoforms Perform the Same Reaction Producing ____ This Links Cell Receptors to Increases in __________________ In Terminal Knobs of Nerve Cells, Another Method of Calcium Increase is Used; Nerve Impulse Depolarization Leads to Opening of Membrane ________________________ Channels This Allows into the Cytoplasm, Calcium from the Extracellular Fluid, Triggering ______________________ Depending on the Type of ____________________:- Calcium Release from the ER can Occur in an ________________________ Fashion Or Calcium Release can be _________________________ In the ER there are 2 Types of ______________________
________________ Mentioned Earlier

The Second Kind are _____________________ (RyRs) that Bind the Toxic Plant
Alkaloid Ryanodine
RyRs are Found Predominantly in _________________ (Mainly Nerves or Muscle) RyRs Open to Increase Cytoplasmic Calcium With the Arrival of an _____________ Mutations in Cardiac Muscle RyRs are Linked to ______________ During Exercise Depending on Cell Type, RyRs Can Also be Opened by _________________ Including Calcium Itself The Influx of a _____________________ from Plasma Membrane Channels Induces Opening of RyRs in the ER
This is Known as ________________________________ (CLCR)
One thing that Makes this Work Well is the _______________ of the ER to the Plasma Membrane In Some Cases the Calcium Spreads to __________________________ In Other Cases Calcium ____________________ One of the Most Dramatic Calcium Waves Occurs ___________________ After the Sperm Penetrates the Egg The Calcium Triggers _________________________ that Allow the Zygote to Proceed Towards its First Cell Division Calcium Waves are Transient as Calcium is ____________________ of the Cytoplasm, into the ER or Out of the Cell After Repeated Stimulations Calcium Stores in the ER Can Become __________
This Triggers a Response Known as _________________________(SOCE)
In SOCE ER Calcium Depletion Triggers the Opening of __________________ Calcium Channels Calcium Entering the Cytosol is _____________________ SOCE Occurs due to a ____________________ Between the ER and Plasma Membrane As ER Calcium is Depleted the ER Protein ________________ Plasma Membrane Calcium Channels Cluster The Clusters Occur at Locations where the ER and Plasma Membrane are _________________________ STIM1 then Interacts With Ora1 to ______________________
Calcium Binding Proteins
Unlike cAMP whose Effect is Usually Mediated by PKA, Calcium Ions have a ___________________________ 2) Change the ______________________ to Ions 4) Alter Cytoskeletal ___________________
Calcium Doesn’t Do this Itself but Acts by Binding ________________________

The Best Known of these is ________________ (CaM; see Figure)
CaM is _________________ in Plants Animals and Microbes There is Not Normally ________________________________ for CaM to Bind However When Calcium Concentration Rises in Response to Stimulation, CaM Binds Calcium and ______________________ This Increases CaMs Affintity for ______________ 2) Cyclic Nucleotide ____________________ 4) The Calcium Transport System of the ________________ No. 4 _____________________________________ as a Form of Self Regulation This Helps Keep Cytoplasmic _________________ Calcium-CaM can Also Effect _______________ This Happens Through Activation of Protein Kinases (___________) ________________ Phosphorylate Transcription Factors One Example, is the Phosphorylation of ________ on the Same _________________
Pathway Crosstalk
__________________ are More Complicated than Showed so Far Signals From _______________ Each Binding its Own Ligand can Converge to Activate _________________________________________ Signals from the Same Ligand (e.g. EGF or Insulin) Can Diverge and Activate ________________________________________ Signals can go _____________________________ (Crosstalk) Signals from _____________________ Enter the Cell Signals from Receptors Get Selectively ________________________________ to Cause a Cell Response The Cell Therefore Integrates Information from a Variety of Sources into an _______________________________________
Convergence
Although Receptors Such as Integrins are Different from GPCRs or RTKs, they Can All Lead to the Formation of ___________________________________________ of the Protein Grb2 The Grb2-Sos Complex Results in ________________________________________ Diverse Receptors Leading to ____________________________________________
Divergence
This Slide from Earlier Illustrates How a _________________ Such as a Ligand Binding to a GPCR or Insulin Receptor Sends Signals Along _____________________
Crosstalk
Signal Transduction Pathways in the Cell Operate More Like an ___________________ cAMP was Earlier Shown to _____________________________ However it Can Also _____________ in Various Cells Such as Fat Cells and Fibroblasts It Inhibits Growth in these Cells by Blocking (Via PKA) Signals Transmitted Through the __________________ PKA can Phosphorylate and ____________________ The Two Pathways Also Cross in the Nucleus Concerning the __________________ The MAP Kinase Pathway (via ______________) can Phosphorylate the Same Ser133 Residue as PKA Therefore cAMP and MAP Kinase Pathways Should _________________________ The Remaining Question is How Do Different _________________________ Using Similar Pathways? The Answer is _______________ Have __________________________
The Role of NO
The Last Signaling Molecule we will Cover was Originally Called ____________________________________ This Molecule (EDRF) that ____________________________ was Eventually Discovered by Ignarro and Moncada, to be ________________ The _________________________ Response is Shown in the Figure 1) ___________________________ on the Blood-Side (Lumen of Vessel) of the Endothelial Cell 2) This Produces a ________________________________ 3) The Rise in Intracellular Calcium ______________________, which Converts the Amino Acid _____________________ (Normally a Gas) 4) Nitric Oxide ______________________ into Adjacent Smooth Muscle Cells 5) In the Smooth Muscle Cells the ____________________________________________________________ Soluble (Cytoplasmic) Guanylyl Cyclase __________________________________________________ PKG Phosphorylates Effector Proteins that ________________________ Nitrogenous Compounds Such as the Inhibitor ______________________ have Similar Effects as they are Converted to NO Nitroglycerine is Used to _______________ as it Relaxes Cardiac Blood Vessels Allowing More Blood Flow This was Discovered from Studies on ___________________ The Discovery of NO as a Second Messenger Also led to _____________________ This was Originally Developed as a ________________________ But it was Realized NO Also Relaxes the ________________________________ Leading to Increased Blood Flow and Greater Male Performance Viagra and Related Drugs ____________, are __________________________ They Inhibit cGMP Phosphodiesterase Enzyme that _________________ Viagra, Levitra and Cialis All Inhibit the cGMP Phosphodiesterase ____________ which is Expressed in Penile Tissue Unfortunately They ____________________ which is ___________________ (Other Inhibitors Can Do that) NO is Now Also Known to be Involved in _____________________ i.e. Addition of NO to SH Groups of Cysteine Amino Acids Proteins’ Post-translationally Modified by S-nitrosylation Include ___________________________________________________ (Involved in Apoptosis).

Source: http://www.bio.georgiasouthern.edu/Bio-home/Cutler/Chapter15Notes.pdf

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Expert Opinions Rheumatology Issue 2 The PCR Society Guide to Commissioning Musculoskeletal Services September 2011 Acknowledgements This guide is the result of a joint initiative between the Primary Care Rheumatology (PCR) Society, the Arthritis and Musculoskeletal Alliance (ARMA), the British Society for Rheumatology(BSR) and the British Orthopaedic Association (BOA

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