Intracellular Signaling Pathways

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intracellular signaling reactions

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ion transport, metabolism, gene expression, cell movement

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cytokines

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polypeptides as autocrine or paracrine regulators

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hormones

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secreted by endocrine glands as polypeptides or steroids as autocrine or paracrine regulators

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used by intracellular receptors

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steroid hormones, derivatives of vitamin D3, retinoic acid and thyroid hormone

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effects of binding of a molecule to a receptor

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second messenger cascade, change in membrane potential, enzyme cascade

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Four major classes of cell surface receptors

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ligand-gated ion channel, enzyme-linked, cytokine, G-protein coupled

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example of a ligand that evokes multiple responses

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acetylcholine- relaxation in cardiac muscle by G-protein or contraction in skeletal muscle by ion channel

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effectors

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signaling proteins( enzymes or ion channels) that react with a receptor

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G-proteins

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coupling proteins between receptors and effectors

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second messengers

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Ca, AMP, GMP, DAG, IP3

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most pathways of intracellular transduction use this to alter protein function

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phosphorylation

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most protein kinases phosphorylate these

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serine, threonine or tyrosine residues

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phosphatases

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remove phosphate and inactivate proteins

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ways cells terminate signal transduction

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reducing ligand availability, degradation of receptor complex, receptor inactivation

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Function of N and C terminals in enzyme-linked receptors

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N- extracellular and contain binding domain;C- intracellular and contain domain for catalytic activity

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receptor tyrosine kinases

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enzyme-linked receptor, component of receptor protein

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dimerization of receptor tyrosine kinases have these effects

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activates the kinase domain, triggers endocytic internalization of the growth factor/receptor tyrosine kinase complex resulting in degradation

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Ras

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GTPase critical in cell proliferation; present in 30% of human tumors; bind to and stim. serine/threonine kinases and trigger MAP cascade

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MAP

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mitogen activating proteins; stimulate mitotic activity

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transforming growth factor B and bone morphogenic proteins

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families of growth regulatory factors required for fetal and neonatal dev. and maintenance of differentiated phenotype in adults

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mutations in these receptors cause progression of cancer

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transforming growth factor B and bone morphogenic proteins

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these growth factors cause dimerization and activation of serine-threonine kinases

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transforming growth factor B and bone morphogenic proteins

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SMAD's

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part of serine-threonine kinase cascade; translocate to nucleus and bind to DNA regulatory seq.

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interleukins and interferons

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cytokines

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plasma receptors for cytokines lack these

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tyrosine or serine/threonine kinase activity- bind nonreceptor tyrosine kinases which are soluble proteins

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STAT's

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signal transducers and activators of transcription- gene reg. protein binding to phos. cytokine receptor- translocate to nucleus, bind to DNA and activate genes

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NFkB

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activated by cytokine receptors- can regulate any gene

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alpha subunits of G proteins

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guanine nucleotide binding site, GTPase activity and effector domains

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G-protein subunits

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alpha, beta and gamma- 20 types of alpha-specifies G-protein

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G-protein stimulation

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GDP occupies nucleotide binding site at rest-GPCR binds ligand-GDP released, GTP binds and alpha subunit leaves

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termination of GPCR pathway

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phosphorylation of receptor by kinases like PKA

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breakdown of cAMP

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catalyzed by cyclic nucleotide phosphodiesterases (PDE's) that hydrolyze cyclic diester bond to make AMP

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stim of adenylyl cyclase

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alpha s subunit of G-protein-inc. in cAMP

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cAMP pathway

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bind to PKA and break tetramer-kinase sites activated-moves to nucleus-phosphorylates cAMP-regulated gene regulatory proteins(CREB)

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these facilitate PKA translocation to the nucleus

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nuclear localization sequences

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what does cGMP regulate

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cellular contractility and blood volume homeostasis

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regulation of cGMP levels

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guanylate cyclase-synthesis
cGMP phosphodiesterases-degredation

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are guanylate cyclases membrane bound or free

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either

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where to find membrane bound guanylate cyclases

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cells which express receptors for ANF-vascular smooth muscle and renal

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what happens when the NO in guanylate cyclase binds heme

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catalytic activity is increased leading to cGMP formation

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phospholipase C

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an enzyme that generates IP3 by hydrolyzing inositol phospholipids-stim. by hormones or neurotransmitters

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phospholipase D

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enzymes that hydrolyze choline or ethanolamine phospholipids-phosphatidic acid-diacylglycerol

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phospholipase A2

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enzymes that catalyze phospholipids producing free fatty acids-arachidonic acid

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DAG

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second messenger that binds and activates protein kinase C

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crosstalk

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integration of signals between cells from extracellular stimuli-causes variation in pathway response due to other pathways