Cell Signaling Flashcards
Steps in cell signaling
- Synthesis of signaling molecule by signaling cell
- Release of the aforementioned signaling molecule
- Transport of the signal to target cell
- Detection of signal by specific receptor of target cell
- Change in function of proteins in target cell, triggered by the receptor-signal complex
- Termination of the signal, which usually terminates the cellular response
Types of signaling mechanisms
Broad classification
- Intercellular signal transduction
- Intracellular signal transduction
Intercellular: endocrine, paracrine, autocrine, and juxtacrine
Intracellular signal transduction
Cell signaling
Comprises the biochemical decoding of the signal upon receipt by a target cell, a process that involves stepwise regulation of intracellular signaling proteins
Types of intercellular signal transduction
- Endocrine
- Paracrine
- Autocrine
- Juxtacrine
Endocrine signaling
Specialized endocrine cells produce hormones which circulate in the bloodstream and can act on diverse and distant targets
Paracrine signaling
Local secretion of mediators by cells. These mediators are rapidly taken up, destroyed or sequestered such that they act only on nearby cells. Synaptic or neuronal signaling+
Autocrine
Cells may secrete a molecule to which they themselves respond
Juxtacrine
Aka contact-depedent signaling - specific cell surface proteins (plasma membrane-attached/anchored) are recognized by receptors expressed on an adjacent cell.
Polypeptide Hormones
Insulin and glucagon
List the classes of hormones
- Polypeptide hormones
- Catecholamines
- Steroid hormones
- Thyroid hormone
Neurotransmitters
Synthesized and stored in nerve terminals. When released the interact with receptor-gated ion channels to mediate rpid responses. Mostly small, simple molecules such as amino acids, substituted amines, and nucleotides
Neuropeptides (neurohormones)
Affect the response of neurons to neurotransmitters. These molecules also have hormone-like affects
Ex: Endorphins and enkephalins that regulate pain sensation
Growth factors
Proteins that bind to receptors on the target cell surface and primarily activate cellular proliferation and/or differentiation. Many GFs are quite versatile, stimulating cellular division in numerous different cell types, while others are specific for a particular target cell type.
Cytokines
Are a unique family of growth factors released by immune cells and are particularly important in both innate and adaptive responses as well as the activation of phagocytic cells.
- Lymphokines - secreted by lymphocytes
- Monokines - secreted by monocytes or macrophages
- Interleukins - IL1-IL35
- Chemokines - cytokines that mediated chemoattraction between cells. Responsible for the homing of leukocytes to site of infection/inflammation.
Local mediators
Involved in paracrine/autocrine signaling
- Eicosanoids
- Platelet activating factor (PAF)
- Lysophopholipids
- Nitric oxide (NO)
Eicosanoids
Derived from arachidonic acid (prostaglandins, thromboxanes, and leukotrienes)
Local mediator
Platelet activating factor (PAF)
A potent phospholipid activator released directly from cell membranes that mediates a wide range of potent and specific biological effects including platelet aggregation, inflammation, and anaphylaxis
Lysophospholipids
Novel class of mediators that include lysophosphatidic acids (LPA) and sphingosine 1-phosphate (S1P) that evoke a wide range of biological responses
Nitric oxide
A gas that diffuses freely across cell membranes. NO is biosynthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by reduction of inorganic nitrate. NO interacts with many molecules and is quickly consumed close to where it is synthesized (autocrine/paracrine)
Group I signaling molecules
Lipophilic and easily diffuse through cell membranes
Bind to intracellular receptors that act directly on gene transcription (i.e. estrogen and progesterone receptors
Group II signaling molecules
Hydrophilic - cannot diffuse through plasma membranes
Bind to transmembrane proteins that act as cell surface receptors (initiate signaling cascades which produces the cellular response via second messenger systems
G-protein coupled receptors (GCPR)
Seven transmembrane receptors (largest class of receptors)
Act through heterotrimeric GTP-binding proteins (G-proteins) to regulate activity of effector enzymes to produce secondary messengers
Or they act as ligand activated ion channels (as a rule - most small molecules and peptides (8-12 a.a.) hormones activated GPCRs)
Secondary messengers
Regulate the activity of various effector proteins - such as kinases and phosphatases which then regulate the activity of other proteins
- Calcium
- Cyclic AMP (cAMP)
- Cyclic GMP (cGMP)
- Phophatidylinositides
- Diacylglyceride
Ligand-gated ion channels
Aka transmitter-gated ion channels - ionotropic receptors and neurotransmitter receptors
Ion channels that open or close in response to binding of a chemical messenger. Such receptors located at synapses convert the chemical signal of presynaptically released neurotranmitter directly and very quickly into a postsynaptic electrical signal
Tyrosine kinase-linked receptors
Lack enzymatic activity, but when bound by a ligand they associate with and activate and intracellular tyrosine kinase which acts on intracellular proteins to alter their activities.
Most cytokines signal via tyrosine kinase-linked receptors coupled to the JAK/STAT pathway
Receptor guanylate cyclase
i. Receptors with an intracellular guanylate cyclase domain
ii. Activation of the cyclase domain increases cGMP, as a second messenger
iii. Only two:Atrial natriuretic factor (ANF) receptors and guanylin receptors
Receptor tyrosine phosphatases
i. Receptors with and intracellular tyrosine phosphatase domain
ii. Activation of the domain removes phosphate groups from tyrosine side-chains in proteins to alter their functions
Receptor serine/threonine kinases
i. Receptors with an intracellular serine/threonine kinase domain
ii. Ligand binding activates the ser/thr kinase domain
iii. Receptors for transforming growth factor beta (TGF-beta) and bone morphogenic protein (BMP) families
iv. Regulate activity of SMAD transcription factors
Receptor tyrosine kinases (RTKs)
i. Receptors with an intracellular
tyrosine kinase domain. Ligand binding activates the kinase domain.
ii. Signaling involves adaptor proteins to connect to diverse signaling pathways such as the RAS/MAP kinase pathway
iii. Well known examples = insulin receptor and epidermal growth factor (EGF) receptor family
iv. In general, polypeptide (50-400 a.a.) growth factors activiate RTKs
Detection of the signaling molecule by a target cell receptor is coupled to processes that cause either:
Target cell responses to signaling molecules
- An immediate change in cellular metabolism by activating or inhibiting enzymes or stimulating the uptake of metabolites
- The opening or closing of ion channels resulting in a change in the electrical charge across the plasma membrane
- A change in gene expression
Mechanisms that terminate or attenuate response to various signaling molecules
- Reducing the signaling molecules availability in the extracellular space
- Internalizing and degrading the receptors
- Rapidly modifying the receptor (e.g. phosphorylation) so that it becomes inactive or desensitized
- Activating the expression of a gene coding for an inhibitor of the signaling pathway
General mechanism of steroid hormone signaling
Pathway diagram
Hormone response element
Aka HREs - The receptor-hormone complex alters transcription of susceptible genes by binding (as homo/heterodimers) to regulatory gene sequences collectively known as HREs
Glucocorticoid response element (GRE)
Estrogen response element (ERE)
Vitamin D response element (VDRE)
Nuclear receptor response roles
- Reproduction - estrogen receptors, progesterone receptors, androgen receptors
- Glucose metabolism and stress - glucocorticoid receptor (GR)
- Mineral balance - mineralcorticoid receptor (MR)
- Thyroid function - thyroid hormone receptor (TR)
- Lipid metabolism - liver x receptor (LXR) and peroxisome proliferator-activated receptors (PPARs)
Common modular structure of all NR’s
- N-terminal transactivation domain
- A central DNA binding domain, containing two zinc finger DNA binding motifs
- A C-terminal ligand/hormone-binding domain
What nuclear receptor subclass form homodimers that bind to inverted repeat elements?
Steroid receptor subclass (GR, MR, PR, AR, and ER)
NR activation/repression of gene transcription
Activation - due to the recruitment of co-activator proteins by the hormone-receptor complex (co-activators often have HAC activity)
Repression - is due to the recruitment of co-repressors by some unliganded nuclear receptor (co-repressors often have HDAC activity)
Mifepristone (RU486)
Antagonist of progesterone receptors
Thiazolidinedion (TZD) derivatives
Rosiglitazone (Avandia), pioglitazone (Actos)- are usued as antidiabetic drugs. TZDs bind to peroxisome proliferator-activated receptor (PPAR)-ƴ, which forms heterodimers with retinoic acid receptor (RXR) and binds to PPREs in the promoters of genes inolved with control of glucose and lipid metabolism in muscle, adipose, and liver.
Selective estrogen receptor modulators (SERMs)
Tamoxifen and raloxifene - Fx as agonist or antagonists of estrogen receptors depending upon cell type. Used to treat estrogen-dependent breast cancers.
Tamoxifen binds to ER but does not induce the same conformational change as estrogen that is necessary for interaction with co-activator proteins
General principles of hormone signaling disorders
- Excessive hormone production
- Insufficient hormone production
- Receptor defects and/or downstream defects (sometimes referred to as “hormone resistance”)
What is the biologically active thyroid hormone
T3 - tri-iodothyronine
Functions - increase oxidative metabolism and increase basal metabolic rate (BMR)
Analogy: thyroid gland functions as the body’s thermostat (turned up - burn more fuel and prouduce more heat)
Thyroid hormone synthesis
Synthesized by follicular cells in the thyroid gland by iodination and coupling of tyrosines in thyroglobulin by tyrosine peroxidase (TPO)
Thyroid gland secrete mostly T4 -> peripheral tissues deiodinate T4 to produce circulating T3
Hypothalmic-pituitary-thyroid axis
Diagram
Hypothyroidism
sxs: Weakness, fatigue, and lethary due to diminished utilization of oxidative fuels
Cold intolerance due to reduced BMR and reduced heat production
Weight gain due to stored fuels not being utilized
Dry skin and coarse hair due to reduced metabolic activity of sebaceous glands
Elevated LDL (LDL_C) due to redueced LDLR expression in liver (LDLR gene is upregulated by thyroid hormone)
What removes LDL from circulation?
LDLR on hepatocytes bind and internalize LDL_C removing it from the blood
Hypothyroidism Tx
Levothyroxine (synthetic T4)
Iodine supplement for iodine deficiency
Surgery for tumors
Immune modulation for autoimmune conditions
Management of other hormone deficiencies for secondary or tertiary hypothyroidism cases, if present
Types of hypothyroidism
Primary hypothyroidism (↓T3/T4→ ↑TSH): Hashimoto’s thyroiditis, iodine deficiency
Secondary hypothyroidism ( ↓TSH → ↓T3/T4): pituitary defect
Tertiary hypothyroidism( ↓TRH→↓TSH →↓T3/T4): hypothalamus defect
Iodine deficiency
Dx: Low T4, elevated TSH, and low urinary iodine
Tx: iodine supplementation
Primary hypothyroidism
Hasimoto’s thyroiditis
~90% of hypothyroidism
Dx: low T4 and elevated TSH, + for anti-thyroid antibodies (anti-TPO and/or anti-thyroglobulin antibodies)
Tx: HRT w/ levothyroxine
Primary hypothyroidism
Secondary hypothyroidism
Causes: pituitary tumors or damage from surgery/radiation therapy
Dx: low T4, low TSH, negative for anti-thyroid antibodies
Dx: may require more specialized tests and MRI
Hypothyroidism due to hypothalamus defect
Causes: Tumors (especially craniopharyngiomas) and TBI causing broad hypothalamic dysfunction
Dx: low/low-normal T4, low or inapporpriately normal TSH, low TRH (requires specialized testing/imaging)
Tertiary hypothyroidism
Hyperthyroidism
Dx and Tx
sxs:
Weight loss (despite normal appetite) due to increased BMR,
Tachycardia, nervousness, anxiety, due to increased expression of of β-adrenergic receptors causing an enhanced response to catecholamines
Perspiration and heat intolerance due to increased BMR
Goiter may develop in some cases
Tx:
Methimazole and propylthiouracil inhibit thyroid peroxidase (TPO), and enzyme crucial for thyroid hormone synthesis
Thyroidectomy or ablation w/ radiotactive iodine therapy (Pt’s require daily oral levothyroxine afterward)
Immunosupression for autoimmune disorders
Types of hyperthryoidism
- Primary: Graves disease, toxic multinodular goiter, toxic adenoma
- Secondary: TSH secreting pituitary tumors
- Tertiary: Hypothalmic dysfunction
Grave’s disease
60-80% of hyperthyroidism
Autoimmune disorder in which auto-antibodies stimulate secretion of thyroid hormones
Dx: high T4 and low TSH (due to negative feedback), positive for anti-TSH receptor antibodies (stimulate the TSH receptor activity)
Sxs: Exopthalmos is common (results from the underlying autoimmune disease affecting volume of the orbital soft tissues - antibodies stimulate fibroblasts in the eye)
Tx: immunosuppressive drugs (corticosteroids) are needed to treat exopthalmos
Primary hyperthyroidism
Toxic multinodular goiter
aka Plummer’s disease
Results from multiple autonomously functioning nodules in the thyroid - develops gradually over many years
Dx: high T4 and low TSH, imaging studies (US or radioiodine uptake scans)
Primary hyperthyroidism
Toxic adenoma
A single hyperfunctioning thyroid nodule that produces excess thyroid hormones
Dx: high T4 and low TSH, imaging studies (US or radioiodine uptake)
Primary hyperthyroidism
Secondary hyperthyroidism
Causes: pituitary tumors secreting TSH (aka “central hyperthyroidism”)
Dx: high T4 and high TSH, MRI
Tertiary hyperthyroidism
Causes: hypothalmic dysfunction - extremely rare and not well-documented in medical literature
Dx: high T4 and high TSH (TRH is not routine thyroid blood testing but would be elevated)
Dx require imaging and specialized testing of hypothalmic-pituitary-thyroid axis
Regulation of cortisol secretion
Diagram
Glucocorticoids
Cortisol
Fx: promotes gluconeogensis, enhances protein breakdown, stimulates lipolysis. A counter-regulatory hormone (oppose the effects of insulin and raises blood glucose)
Immunosuppressive effects
Corticosteroids
Mineralcorticoids
Aldosterone
Fx: promotes Na reabsorption and K excretion in the kidney
Hypothalamus-pituitary-adrenal axis
- Hypothalamus releases corticotropin releasing hormone (CRH)
- CRH stimulate anterior pituitary to release of adrenocorticotropic hormone (ACTH)
- ACTH stimulates adrenal cortex to produce cortisol
- Cortisol binds to glucocorticoid receptors (GR) inside cells and alters transcription of genes containing GREs
- Cortisol provides negative feedback to hypothalamus and pituitary (↓CRH and ACTH production)
Aldosterone regulation
Release of aldosterone from the adrenal glands is primarily stimulated by factors within the renin-angiotensin-aldosterone system (RAAS)
Aldosterone binds to the mineralcorticoid receptor (MR) which then alters transcription of genes with MREs
Hypocortisolemia
Aka adrenal insufficiency
Sxs:
fatigue, anorexia, hypoglycemia due to low gluconeogenesis
Hyponatremia, hyperkalemia due to low aldosterone
Hyperpigmentation (darkening of the skin and mucous membranes) if ACTH is very high
-ACTH has similarity with melanocyte-stimulating hormone (MSH) and stimulate production of melanin
Tx:
Low cortisol: HRT w/ hydrocortisone or prednisone (synthetic glucocorticoids)
Low aldosterone: HRT w/ fludrocortisone (synthetic mineralcorticoid) and maintenance of sodium intake
Management of other hormone deficiencies if present and Tx of underlying cause if possible
Primary hypocortisolemia
Addison’s disease (destruction of adrenal cortex by infectious disease - i.e. TB or autoimmune
Dx: low cortisol, low aldosterone, high ACTH
No response to ACTH stimulation test - synthetic ACTH (cosyntropin) is given IV and cortisol levels are measured. A normal response is a significant increase in serum cortisol.
Secondary hypocortisolemia
Secondary adrenal insufficiency: pituitary defect (tumor, TBI, surgery or radiation)
Dx: low cortisol and low ACTH
inadequate or subnormal response to ACTH stimulation test - adrenal glands have often atrophied due to long-term lack of ACTH stimulation
Electrolytes (Na and K) are typically normal (aldosterone is not strongly regulated by ACTH)
May show levels of other pituitary hormones (hypopituitarism)
Tertiary hypocortisolemia
Hypothalamus defect
Often part of broader hypothalamic dysfunction due to tumors, TBI, radiation
Dx: low cortisol, low-normal ACTH (depending on severity of hypothalamus defect)
Normal response to CRH stimulation test - ACTH and cortisol levels increase after CRH administration. This response distinguishes tertiary from secondary adrenal insufficiency
Hypercortisolism
Cushing’s syndrome
Sxs:
Muscle weakness, skin thinning, stretch marks due to protein breakdown
Hyperglycemia due to ↑ gluconeogenes
Hypertension due to ↑ sodium retention and consequent water reabsorption coupled with enhanced sensitivity of blood vessels to catecholamines
Hirutism due to stimluation of androgen production
Iatrogenic hypercortisolism
Result of receiving high doses or long-term tx w/ corticosteroids
Primary hypercortisolism
aka ACTH-independent Cushing’s syndrome
Causes: adrenal tumor produces excess cortisol, independent of pituitary control
Dx: high cortisol, low ACTH (suppressed by - feedback)
No response to Dex suppression test - Dex is a potent synthetic glucocorticoid that, under normal conditions, supresses ACTH production in the pituitary and lowers cortisol. Failure to supress indicates source of cortisol is not responsive to pituitary feedback mechanisms
Noninvolved adrenal gland may atrophy due to lack of ACTH stimulation
ACTH-producing pituitary tumors
Cushing’s disease
Dx: high cortisol and high ACTH (usually not as high as in Addison’s disease, so no hyperpigmentation)
A low dose dex (1mg) will not suppress cortisol, but a high-dose dex (8mg) does - the pituitary tumor retains some sensitivity to negative feedback
Secondary hypercortisolism
Ectopic ACTH-producing tumors
i.e. small cell lung cancer - Cushing syndrome not disease
Dx: high cortisol and high ACTH (usually not as high as in Addison’s disease, so no hyperpigmentation)
Cortisol not supressed by low or high-dose dex. The tumore produces ACTH autonomously
Both adrenals can be enlarged due to persistent stimulation by ACTH
Secondary hypercortisolism
Tertiary hypercortisolism
Hypothalmic dysfunction → ↑CRH
Causes: long-term exogenous glucocorticoid use leads to supression of the hypothalamic-pituitary-adrenal (HPA) axis. Upon withdrawal of exogenous steroids, the hypothalamus may overproduce CRH. This leads to excessive ACTH production by the pituitary and subsequently increased cortisol production by the adrenals.
Dx: may involve CRH stimulation tests and careful monitoring during steroid tapering
Tx: gradual tapering of exogenous glucocorticoids. Temporary replacement w/ shorter-acting glucocorticoids
Nuclear receptor defects
Inherited defects are rare but clinically significant
Sxs: resemble hormone deficiency, despite elevated hormone levels
Tx: if the inactivation is partial, the condition can sometimes be treated w/ high doses of hormones
- Generalized thyroid hormone resistance - mutations in the TR gene that reduces T3 binding - hypothyroidism sxs w/ high T3/4 levels and high TSH (- feedback mech needs function TR to work correctly)
- Glucocorticoid receptor deficiency - loss of Fx mutations in the GR gene (Addison’s disease-like sxs w/ high cortisol)
Nitric Oxide
Synthesized by the deamination of arginine by NO synthase
Activates a cytosolic guanylate cyclase resulting in the production of the second messenger cyclic guanosine monophosphate (cGMP)
Increase in cGMP levels activated cGMP-dependent protein kinases, culminating in a reduction in intracellular Ca2+ conc. and decrease to the sensitivity of the contractile system to Ca2+
NO signaling during SMC relaxation
Diagram
Sildenafil/tadalafil/vardenafil
Selectively inhibit the type 5 PDE (PDE5) - highly express in vascular smooth muscle cells.
Viagra is less selective for most other types of PDE, like PDE3 (predominantly expressed in cardiac muscle). However, sildenafil is only slightly more selective for PDE5 than for PDE6, the predominant PDE in light-sensing cells of the retina
Thus, slight overdoses of sildenafil can cause mild alterations in visual color perception due to inhibition of retinal PDE6, which manifests as cyanopsia (blue-tinted vision)
Nonarteritic anterior ischemic optic neuropathy
There have also been at least 14 reported cases of temporary blindness associated with Viagra use due to nonarteritic anterior ischemic optic neuropathy. It is thought that these cases arise because the optic nerves are pinched by Viagra-induced dilation of ophthalmic arteries in the optic foramen.
GPCRs
7 transmembrane helices
Activate heterotrimeric guanine-nucleotide binding proteins (G-proteins) to control specific effector proteins
G-proteins
Have three subunits (α, β and γ)
When activated - G-protein interacts with an effector protein which produces a 2nd messenger moecule (effector proteins are usually enzymes or ion channels)
α subunits can bind GDP or GTP
-αGDP is inactive
-αGTP is active
Agonist binding to a GPCR results in a conformational change that promotes interaction with an inactive G-protein (αGDPβγ). - induces conformational change that promotes interaction with inactive G-protein αGTP dissociates from βγ and interacts with an effector protein altering its activity
α contains an intrinsic GTPase activity which hydrolyzes GTP to GDP. The α-GDP then reassociates with βγ to form an inactive αGDPβγ complex. The GTPase activity functions as a self-timer or “auto-off” switch for the α subunit.
Major G-protein families
The 3 major Gα families: αs, αi,αq (aka Gs, Gi, and Gq)
Gs and Gi modulate adenylate cyclase to alter levels of 3’,5’-cAMP:
Gs - stimulates adenylate cyclase to increase cAMP
Gi - inhibits adenylate cyclase to decrease cAMP
Degradation of cAMP
cAMP is degraded by cAMP phosphodiesterases - in the absence of Gs signaling cAMP levels levels are kept low. Rapid formation and degradation of 2nd messengers allows for rapid on/off control
-Methyl xanthines, like caffeine and theophylline, inhibit cAMP phosphodiesterases and pontentiate the effects of GCPRs coupled to Gs. (Note: the primary physiological effects of caffeine are due to antagonism of adenosine receptors in the CNS)
The net adenylate cyclase activity in a cell
is the result of simultaneous action of Gs and Gi signals
cAMP-dependent protein kinase A (PKA)
Activated by cAMP
PKA is a tetramer with two regulatory (R) and two catalytic (C) subunits
When cAMP levels rise, cAMP binding sites in the R subunits become occupied and the C subunits dissociate as active ser/thr kinases
PKA regulates the activites of secondary kinases and phosphatases, with change pohsphorylation states of various enzymes turning them on or off. A classic example is regulation of glycogen synthesis and breakdown in the liver
PKA regulation of glycogen synthesis and breakdown in the liver
Figure
Active PKA inactivated glycogen synthase
Posphorylation of cAMP-regulatory element binding protein (CREB)
Performed by PKA - phosphorylated CREB binds to specific DNA sequences, cAMP regulatory elements (CRE), in the promoters of some genes to produce changes in gene expression
Gq (aka GP or GPLC)
Activates phospholipase C (PLC).
PLC cleaves phosphatidyl inositol bisphosphate (PIP2) in the membrane giving rise to 2nd messengers:inositol triphosphate (IP3) and diacylglycerol (DAG)
IP3 diffuses in the cytosol and binds to IP3-gated Ca2+ release channels on Ca2+ storage organelles (sarcoplasmic and endoplasmic reticulum) causing an increase in cytosolic Ca2+ which activates calcium-dependent processes
A) Cushing’s syndrome
B) Hypothyroidism
C) Grave’s disease
D) Addison’s disease
Cushing’s syndrome
A mutation in the Gs protein increases the rate of GTP hydrolysis. How would this mutation most likely affect protein kinase A (PKA) activity?
Decrease PKA activity
In many cells, epinephrine will bind to alpha-1 adrenergic receptors resulting in activation of the Gq signaling pathway. Which of the following happens when epinephrine binds alpha-1 adrenergic receptors?
Phospholipase C will be activated
A 48 year old male is diagnosed with type II diabetes mellitus. After evaluating various treatment modalities, you recommend therapy with pioglitazone, a thiazolidinedione (TZD) with affinity for PPAR gamma, a nuclear hormone receptor. Which of the following best describes the mechanism by which pioglitazone therapy exerts beneficial effects?
Modulation of gene transcription
What upregulates LDLR in hepatocytes?
T3 - LDLR gene has a T3 binding region that upregulates expression
Why there are diminished LDLR’s in hepatocytes of someone with hypothyoroidism
A) Phosphorylation of STAT factors
B) GTP/GDP exchange on Ras
C) Dimerization of SMAD factors
D) Activation of Janus kinases (JAK)
Dimerization of SMAD factors
A) Prohpsatidylinositol-3-kinase (PI-3K)
B) Protein kinase B (Akt/PKB)
C) Grb2
D) Ras
A) PI-3K
Goes on to activate Akt and PKC
The mechanism by which Ras operates downstream of an activated receptor tyrosine kinase is most similar to which of the following signaling proteins?
Alpha subunits of heterotrimeric G proteins
Proteins that contain a Src homology 2 (SH2) domain_______________________.
Bind to proteins that have a phosphotyrosine residue within a specific context
Release of atrial natriuretic factor (ANF) by cardiac cells reduces blood volume by regulating the activity of ANF receptors in the kidney. What is the most direct consequence of ANF binding to an ANF receptor?
D) increased production of cGMP
The hematopoietic system is made up of all adult blood cell types including erythrocytes and cells of the myeloid and lymphoid lineages. All these cells are derived from multipotent hematopoietic stem cells (HSCs) through a succession of precursors with progressively limited potential under the control of specific cytokines, such as interleukins and granulocyte/monocyte-stimulating factors. Maturation of HSCs involves which of the following signal transduction events?
C) activation of ctyosolic kinases that phosphorylate STAT proteins
The insulin receptor has in common with many growth factor receptors, such as the epidermal growth factor receptors (EGFR) and the fibroblast growth factor receptors (FGFR), ________________.
A) the ability to phosphorylate tyrosine residues on proteins
Which of the following occurs when epidermal growth factor binds to EGF receptors (EGFR) and activates the RAS/MAP kinase pathway?
Grb2 binds to phosphorylated tyrosine residues of the receptor
A 45-year-old patient with a history of type 2 diabetes mellitus presents to the clinic with complaints of unexplained weight loss, excessive thirst, and frequent urination. Laboratory tests reveal hyperglycemia and glycosuria. The patient’s medical history includes a sedentary lifestyle and a diet high in processed foods. Given the symptoms and history, the physician suspects insulin resistance and decides to investigate the involvement of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Which of the following statements concerning the reaction catalyzed by phosphatidylinositol 3-kinase (PI-3K) is true?
B) phosphaatidylinositol 4,5-bisphophate (PIP2) is a substrate
RAS activation in cells is opposed by the activity of _________________?
E) GTP’ase activating proteins (GAPs)
What kind of activity does an insulin receptor have?
It is a tyrosine kinase
Ras
Bound to GDP - off
Bound to GTP - on
Ctyokine pathway
The JAK/STAT pathway
Blue-tinted vision secondary to taking sildenafil
slight overdoses of sildenafil can cause mild alterations in visual color perception due to inhibition of retinal PDE6, which manifests as cyanopsia (blue-tinted vision).
selectively inhibit the type 5 PDE (PDE5) that is highly expressed in vascular smooth muscle cells. Viagra is less selective for most other types of PDE, like PDE3 predominantly expressed in cardiac muscle. However, Viagra is only slightly more selective for PDE5 than for PDE6, the predominant PDE in light-sensing cells of the retina.
Cholera vs. whooping cough affects on G-proteins
Gs - cholera
Gi - whooping cough
ADP-ribosylation
Pseudohypoparathyroidism (Albright’s hereditary osteodystrophy,
AHO)
