Thewke 2

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G proteins

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are organized with an extracellular amino terminus and coo- intracellular 7tm. transmembrane domains form a binding pocket that contain ligand binding aa. the third loop is esential for g protein binding,. Tail has serine and threonine residues for binding. IMportant for signal termination

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GPCRs

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activate hetrotrimeric GTP binding proteins comprised of a, b, and y subunits. The activated g protein then activates with an effector.

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effector produces

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second messenger, effectors are ussually ion channesl or enzymes.

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a subunit

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has the guanine nucleotide binding site and a GTPASE activity

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when agonist binds to the g protein receptor the

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alpha dissociates from b,y bound to GTP and associates with the effector protein. After done the GTPASE hydrolysez back to GDP, which is converted to GTP when ligan binds again.

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three primary a subfamilies

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next

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stimulate adenylate cyclase increasing cAMP

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As of Gs subfamily

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Ai

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of Gi inhibt adenylate

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Aq

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of Gq subfamily activate phospholipase C which increases the second messengers IP3 and DAG.

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Gby of Gia

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inhibits the Gs proteins and thus adenylate cyclase indirectly by binding them. the a of the Gi inhibts directly by binding to adenylate cyclase.

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Adenylate cyclase

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has two integral membrane domains that span at least 6 times each. Adenylate has two catalytic domains on the cytosolic side

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cAMP phosphodiesterases

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destroy cAMP rapidly.

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caffiene inhibts

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cyclic AMP phosphodiesterase to 5AMP

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cAMP binds to the two regulatory domains of PKA or cAPK

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and lets them dissociate from their two associated catalytic subunits. Actives phosphoryalte.

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PKA phosphorylates

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CREB, which activates genes containg CRElements that are in the 5' flanking region,

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PLC-B

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g protein linked, PLC-a is insulin linked.

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PLC is activated by a subunit of G protein

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and PLC cleaves PIP2 making IP3 and DAG which are second messengers

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IP3---diffuses freely

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releases calcium, opening an ion channel

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DAG is a membrane bound and works with Ca++

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that activate Protein kinase C which phosphorylates specific protiens, DAG can be made into arachodonic acid which makes eicosanoids.

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IP3 mediated Ca++ release

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uses calmodulin often which has four binding sites and upon binding Ca++ undegoes confor. changes that facilitate interaction with many downstream targets.

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CAM/KInase 2

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is a serine/threonine specific protein kinase regulated bythe Ca++/calmodulin complex. CaM kinase 2 plays a role in many processes, such as neurotransmitter secretion, transcription factor regulation, and glycogen metabolism. Between 1 and 2% of the proteins in the brain are CaM kinase 2.

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Activation of CaM kinase 2

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calmodulin/Ca++ complex initates autophosphorylation of CaM kinase 2 that results in an increase of affinity for Ca++/calmodulin prolonging activity, and continued activated even after calmodulin complexhas dissacoisated.

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cholera toxin ADP-ribosylates

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the a subunit of Gs and inactivates the GTPASE activity and elevates cAMP hundreds fold, can phosphorylate CL- channels that results in severe diahrreah

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Pertussis toxin from pertussis

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adp ribosylates the a subunit of Gi such that GTP cannot be changed fro GDP and thus inhibition of adenylate cyclase is lost and cAMP rise giving whooping cough.

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pseudohypoparathyroidism or AHO

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is a very rare genetic disorder that resembles hypoparathyroidism, which is caused by a lack of response to parathyroid hormone. GNAS1 gene which encodes the Gsa subunit so reduced activty

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acromegaly

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constituitively activated adenylate cyclase in tumor cells due to GNAS1 gene mutation. Majority of mutation have single amino acid substitutions that are critical for GTP hydrolysis. Both mutations decrease the GTPase actvitity of Gsa, one same site as cholera toxin.

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RTK

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upon ligand binding the receptor tyrosine kinases are autophosphorylated at multiple tyrosines. The phosphorylated tyrosines act as high affinity binding sites for a number of intracellular signaling proteins in the target cell

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RTK

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are single pass transmembrane proteins, (insulin receptro has two TM b-subunits) with a ligand binding site in the extracellular side and a catalytic domain on the cytosolic side of the membrane.

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RTK

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recognize peptide protein signals that act as GROWTH FACTORS

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RTK is distinguised by a very

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large cytoplasmic domain

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Bind of the ligand causes most RTKs

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to dimerize. The tyrosine kinases of each monomer then phosphorylates specific tryosines on its partner. The domain with the phosphorylated tyr are called SRC homology domain or SH2

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Some of SH2 are adaptor proteins

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that couple activated receptors to other signaling molecules

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PTB domain

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is the centerpiece between PH and SH2 that binds to the receptro, and is a phosphotyrosine binding domain

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SH2 domain

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binds to specific phosphotyrosines.

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SH3 domain

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binds to a proline rich sequence.

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PH domain

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Pleckstrin homology domain and binds to phosphoinositides.

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proteins that bind to the phosphotyrosines of activated RTK

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are adaptor proteins that recruit and stimulate RAS-activating proteins.

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Ras proteins are an unusual class of GTP binding proteins

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are single polypetides chains with little homology to other G proteins, not modified by bacterial toxins.

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RAS proteins are ubiquitous

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and are intermediaries in signaling transduction

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Ras Protein

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is prenylated, this is a lipid modification that allows for association with the lipid membrane

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RAS

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has an intirinsic GTPase activity

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Activation of RAS invovles the exchange of GTP for bound GDP

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guanine nucleotide exchange factors or GEF accelerate the exchange of GTP for GDP on RAS.

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INactivation of RAS

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involves the binding of a GTPase activating Protein GAP and the hydrolysis of GTP to GDP by the intrinsic GTPASE activity of RAS.

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GRB2 contains an SH2 that binds to RTKs activated

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this then recruits SOS, a GEF, via the interaction of SH3 domains of GRB2 to the proline rich of SOS. SOS then facilitates the exchange of GTP for GDP on Ras, thus activating RAS.

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Signaling transduction by RAS occurs through a series of serine/threonine kinase reactions known as mitogen activated Protein Kinases cascades

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MAP kinases

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initial activated Ras-Kinase

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is MAPkkk or RAF (serine/thronine) which act. Mapkk (mek) which is tyr/ thre/ ser/ and Mapkk activates the terminal Erk or Map Kinase. Mapk or erk then activates genes responsible for cell division, survival, differentiation.

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Ras mutation

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inactivates its GTPase activity and give growth factors allways active

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INsulin receptor---is an RTK however

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but is different in that it contains 2 b and 2 a subunits. When ligan binds to the two extracellular a domains then the Bs are autophosphorylated which recruits IRS1 binding to insulin rreceptor via PTB domain.

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IRS1

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is phosphorylated by the receptora upon binding and is then recognized by the SH2 domain of other proteins. Can signal via Ras, PLC pathway, Pi-3 kinase pathway

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Activation of he Pi-3 kinase/PKB pathway

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regulates blood glucose homeostasis

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In the case above irs1

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activates Pi-3 kinase by binding to its SH2 domain.

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activates PI-3 kinases

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produces PIP3 which acts as a second messenger

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PKB/Akt

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associates with PIP3 via PH domain on the plasma membrane and brings it closer to the phosphatidyl inositol dependent kinases which can then phosphorylate and activate PKB/AKt

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activated PKB

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stimulates the movement of the glucose transporter from internal membrane vesicles to the plasma membrane increasing the uptake of glucose

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EFG receptor HER1 gene, ErbB1

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is overexpressed in may cancers. mutant erbB1 gene produces a receptro lacking the extracellular EGF binding domain, and is highly overexpressed in the glioblastomas

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cetuximab

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is an antibody targeting this receptor that keeps it from being activated for head and neck tumors.

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HER2 binds no known ligands but still autophos.

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and even modest overexprression can alter normal growth. Trastuzumab is an anti-HER2 antibody used fro treatment of breast cancers.

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receptors with intrinsic serine/threonine tyrosine kinase activity

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like TGF-b and BMP receptors. Smad transcription factors act downstream of these.

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TGFb 1 and t receptors

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are dimeric transmembrane proteins with ser/thr kinases on cytosolic domain

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type 2 is always active

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and phosph. itself

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if tgfb binds to type 2

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the type 2 will activate the type1

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activated type 1

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will phosphorylate receptor regulated SMADS which then associate with co-SMADS-drosophilla homologs

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BMP7 used to strengthen

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bones after fractures. Loss of TGF-b smad signaling can induce tumors by removing growth inhibiton.

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guanylate cyclase activity receptors like ANF receptor--hihgly phosphorylated...

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produce cGMP which activates PKG,

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guanylin receptor

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is one of the before receptors and regulate CL- transport in the intestine. Target of heat stable ecoli endotoxin. this toxin inactivates the receptor and results in elevated cGMP levels and increasesthe secretion of Cl- secretion and consequently decreases H20 absorption by intestine and leads to diarrhea,

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receptor with intrinsic tyrosine phosphatase activity is the CD45

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which is on leucocytes and plays a critical role in activation of t and b lymphocytes

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some receptors do not have catalytic activity

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and will associate with cytosolic tyrosine kinases

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tyrosine kinase associated receptors

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upon interaction with ligand interact with nonreceptor tyrosine kinases. the tyrosine receptors they interact with are mostly members of two famalies

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SRC family of kinases they interact with

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are located on the cytoplasmic side of the plasma membraneand have SH@ and SH3 for interaction

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The Janus fmaily kinases they interact wiht

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are associated with receptors for cytokines like IL-2, Il-3, and IFN-y. The janus family includes kinases referrred to as JAK-1 and JAK-2.

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LIgan binding causes receptor dimerization followed by the recruitment of JAKS

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and autophosphorylation of the JAKS, this complex is recognized by STATs via SH2 domain

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STAT phosphorylation

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by JAKS cause them to dimerize and translocate to the nucleus where they activate gene transcription

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INFy via Jak/STAT pathway

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blah

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some cells will express and secrete enzymes which degrade a signal

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ACTH is rapidly degraded by acetylcholnesterases. too high cAMP can induce PKA activation which phosphorylates receptors to reduce interaction.