This document discusses different classes of signal transducing receptors including receptor tyrosine kinases, non-receptor tyrosine kinases, receptor serine/threonine kinases, and non-receptor serine/threonine kinases. It describes how receptor tyrosine kinases contain intrinsic tyrosine kinase domains and transduce signals via autophosphorylation or phosphorylation of other substrates. Non-receptor tyrosine kinases like Src kinases couple to receptors that lack enzymatic activity. Receptor serine/threonine kinases have intrinsic serine/threonine kinase activity like TGF-β receptors and transduce signals via phosphorylation of other receptors.
This document discusses different classes of signal transducing receptors including receptor tyrosine kinases, non-receptor tyrosine kinases, receptor serine/threonine kinases, and non-receptor serine/threonine kinases. It describes how receptor tyrosine kinases contain intrinsic tyrosine kinase domains and transduce signals via autophosphorylation or phosphorylation of other substrates. Non-receptor tyrosine kinases like Src kinases couple to receptors that lack enzymatic activity. Receptor serine/threonine kinases have intrinsic serine/threonine kinase activity like TGF-β receptors and transduce signals via phosphorylation of other receptors.
This document discusses different classes of signal transducing receptors including receptor tyrosine kinases, non-receptor tyrosine kinases, receptor serine/threonine kinases, and non-receptor serine/threonine kinases. It describes how receptor tyrosine kinases contain intrinsic tyrosine kinase domains and transduce signals via autophosphorylation or phosphorylation of other substrates. Non-receptor tyrosine kinases like Src kinases couple to receptors that lack enzymatic activity. Receptor serine/threonine kinases have intrinsic serine/threonine kinase activity like TGF-β receptors and transduce signals via phosphorylation of other receptors.
Receptor Tyrosine Kinases Non-Receptor Tyrosine Kinases Receptor Serine/Threonine Kinases Non-Receptor Serine/Threonine Kinases Phospholipids and Phospholipases G-Protein Coupled Receptors G-Protein Regulators Intracellular Hormone Receptors Phosphatases Return to Medical iochemistry Page Mechanisms of Signal Transduction Signal transduction at the cellular le!el re"ers to the mo!ement o" signals "rom outside the cell to inside# The mo!ement o" signals can $e simple% li&e that associated 'ith receptor molecules o" the acetylcholine class( receptors that constitute channels 'hich% upon ligand interaction% allo' signals to $e passed in the "orm o" small ion mo!ement% either into or out o" the cell# These ion mo!ements result in changes in the electrical potential o" the cells that% in turn% propagates the signal along the cell# More comple) signal transduction in!ol!es the coupling o" ligand-receptor interactions to many intracellular e!ents# These e!ents include phosphorylations $y tyrosine &inases and/or serine/threonine &inases# Protein phosphorylations change en*yme acti!ities and protein con"ormations# The e!entual outcome is an alteration in cellular acti!ity and changes in the program o" genes e)pressed 'ithin the responding cells# Please re"er to the page on Gro'th +actors "or descriptions o" the gro'th "actors descri$ed in this page and the e)planation o" their a$$re!iations# $ac& to the top Classifications of Signal Transducing Receptors Signal transducing receptors are o" three general classes( 1. Receptors that penetrate the plasma mem$rane and ha!e intrinsic en*ymatic acti!ity Receptors that ha!e intrinsic en*ymatic acti!ities include those that are tyrosine kinases ,e#g# P-G+% insulin% .G+ and +G+ receptors/% tyrosine phosphatases ,e#g# C-01 2cluster determinant-453 protein o" T cells and macrophages/% guanylate cyclases ,e#g# natriuretic peptide receptors/ and serine/threonine kinases ,e#g# acti!in and TG+- receptors/# Receptors 'ith intrinsic tyrosine &inase acti!ity are capa$le o" autophosphorylation as 'ell as phosphorylation o" other su$strates# 4dditionally% se!eral "amilies o" receptors lac& intrinsic en*yme acti!ity% yet are coupled to intracellular tyrosine &inases $y direct protein-protein interactions ,see $elo'/# 2. Receptors that are coupled% inside the cell% to GTP-$inding and hydroly*ing proteins ,termed G-proteins/# Receptors o" the class that interact 'ith G-proteins all ha!e a structure that is characteri*ed $y 5 transmem$rane spanning domains# These receptors are termed serpentine receptors# .)amples o" this class are the adrenergic receptors% odorant receptors% and certain hormone receptors ,e#g# glucagon% angiotensin% !asopressin and $rady&inin/# . Receptors that are "ound intracellularly and upon ligand $inding migrate to the nucleus 'here the ligand-receptor comple) directly a""ects gene transcription# $ac& to the top Receptor Tyrosine !inases "RT!s# The proteins encoding RTKs contain "our ma6or domains( 4n e)tracellular ligand $inding domain# 4n intracellular tyrosine &inase domain# 4n intracellular regulatory domain# 4 transmem$rane domain# The amino acid se7uences o" the tyrosine &inase domains o" RTKs are highly conser!ed 'ith those o" c4MP-dependent protein &inase ,$!%/ 'ithin the 4TP $inding and su$strate $inding regions# Some RTKs ha!e an insertion o" non-&inase domain amino acids into the &inase domain termed the &inase insert# RTK proteins are classi"ied into "amilies $ased upon structural "eatures in their e)tracellular portions ,as 'ell as the presence or a$sence o" a &inase insert/ 'hich include the cysteine rich domains% immunoglo$ulin-li&e domains% leucine-rich domains% Kringle domains% cadherin domains% "i$ronectin type III repeats% discoidin I-li&e domains% acidic domains% and .G+-li&e domains# ased upon the presence o" these !arious e)tracellular domains the RTKs ha!e $een su$-di!ided into at least 80 di""erent "amilies# Characteristics of the Common Classes of RT!s Class &'amples Structural (eatures of Class I .G+ receptor% N.9/H.R:% H.R; cysteine-rich se7uences II insulin receptor% IG+-8 receptor cysteine-rich se7uences< characteri*ed $y disul"ide-lin&ed heterotetramers III P-G+ receptors% c- Kit contain 1 immunoglo$ulin-li&e domains< contain the &inase insert I= +G+ receptors contain ; immunoglo$ulin-li&e domains as 'ell as the &inase insert< acidic domain = !ascular endothelial cell gro'th "actor ,=.G+/ receptor contain 5 immunoglo$ulin-li&e domains as 'ell as the &inase insert domain =I hepatocyte gro'th "actor ,HG+/ and scatter "actor ,SC/ receptors heterodimeric li&e the class II receptors e)cept that one o" the t'o protein su$units is completely e)tracellular# The HG+ receptor is a proto-oncogene that 'as originally identi"ied as the Met oncogene =II neurotrophin receptor "amily ,tr&4% tr&% tr&C/ and NG+ receptor contain no or "e' cysteine-rich domains< NG+R has leucine rich domain Many receptors that ha!e intrinsic tyrosine &inase acti!ity as 'ell as the tyrosine &inases that are associated 'ith cell sur"ace receptors contain tyrosines residues% that upon phosphorylation% interact 'ith other proteins o" the signaling cascade# These other proteins contain a domain o" amino acid se7uences that are homologous to a domain "irst identi"ied in the c- Src proto-oncogene ,c - designates the cellular "orm o" proto-onogenes that 'ere "irst identi"ied in trans"orming retro!irus/# These domains are termed S)2 domains ,Src homology domain :/# 4nother conser!ed protein-protein interaction domain identi"ied in many signal transduction proteins is related to a third domain in c-Src identi"ied as the S) domain# The interactions o" SH: domain containing proteins 'ith RTKs or receptor associated tyrosine &inases leads to tyrosine phosphorylation o" the SH: containing proteins# The result o" the phosphorylation o" SH: containing proteins that ha!e en*ymatic acti!ity is an alteration ,either positi!ely or negati!ely/ in that acti!ity# Se!eral SH: containing proteins that ha!e intrinsic en*ymatic acti!ity include phospholipase C- "$*C-#% the proto- oncogene c-Ras associated GTPase acti!ating protein ,rasG%$/% phosphatidylinositol--kinase "$+-!#% protein phosphatase-1C "$T$1C#% as 'ell as mem$ers o" the Src "amily o" protein tyrosine kinases "$T!s## $ac& to the top ,on-Receptor $rotein Tyrosine !inases "$T!s# There are numerous intracellular PTKs that are responsi$le "or phosphorylating a !ariety o" intracellular proteins on tyrosine residues "ollo'ing acti!ation o" cellular gro'th and proli"eration signals# There is no' recogni*ed t'o distinct "amilies o" non-receptor PTKs# The archetypal PTK "amily is related to the Src protein# The Src protein is a tyrosine &inase "irst identi"ied as the trans"orming protein in Rous sarcoma !irus# Su$se7uently% a cellular homolog 'as identi"ed as c-Src# Numerous proto- oncogenes 'ere identi"ied as the trans"orming proteins carried $y retro!iruses# The second "amily is related to the -anus kinase "-ak## Most o" the proteins o" $oth "amilies o" non-receptor PTKs couple to cellular receptors that lac& en*ymatic acti!ity themsel!es# This class o" receptors includes all o" the cyto&ine receptors ,eg the interleu&in-: ,I>-:/ receptor/ as 'ell as the C-0 and C-? cell sur"ace glycoproteins o" T cells and the T cell antigen receptor ,TCR/# This mode o" coupling receptors to intracellular PTKs suggests a split "orm o" RTK# 4nother e)ample o" receptor-signaling through protein interaction in!ol!es the insulin receptor ,IR/# This receptor has intrinsic tyrosine &inase acti!ity $ut does not directly interact% "ollo'ing autophosphorylation% 'ith en*ymatically acti!e proteins containing SH: domains ,e#g# PI-;K or P>C- /# Instead% the principal IR su$strate is a protein termed IRS-8# IRS-8 contains se!eral moti"s that resem$le SH: $inding consensus sites "or the catalytically acti!e su$unit o" PI-;K# These domains allo' comple)es to "orm $et'een IRS-8 and PI-;K# This model suggests that IRS-8 acts as a docking or adapter protein to couple the IR to SH: containing signaling proteins# 4dditional adapter proteins ha!e $een identi"ied% the most commonly occurring $eing a protein termed gro.th factor receptor-/inding protein 20 Gr/2# 4n e)ample o" an alteration in receptor acti!ity in response to association 'ith an intracellular PTK is the nicotinic acetylcholine receptor ,4ChR/# These receptors comprise an ion channel consisting o" "our distinct su$units ,% % % and /# The % % and su$units are tyrosine phosphorylated in response to acetylcholine $inding 'hich leads to an increase in the rate o" desensiti*ation to acetylcholine# $ac& to the top Receptor Serine/Threonine !inases "RST!s# The receptors "or the TG+- super"amily o" ligands ha!e intrinsic serine/threonine &inase acti!ity# There are more than ;@ multi"unctional proteins o" the TG+- super"amily 'hich also includes the acti!ins% inhi$ins and the $one morphogenetic proteins ,MPs/# This super"amily o" proteins can induce and/or inhi$it cellular proli"eration or di""erentiation and regulate migration and adhesion o" !arious cell types# The signaling path'ays utili*ed $y the TG+-% acti!in and MP receptors are di""erent than those "or receptors 'ith intrinsic tyrosine &inase acti!ity or that associate 'ith intracellular tyrosine &inases# 4t least 85 RSTKs ha!e $een isolated and can $e di!ided into : su$"amilies identi"ied as the type I and type II receptors# >igands "irst $ind to the type II receptors 'hich then leads to interaction 'ith the type I receptors# Ahen the comple) $et'en ligand and the : receptor su$types "orms% the type II receptor phosphorylates the type I receptor leading to initiation o" the signaling cascade# Bne predominant e""ect o" TG+- is regulation o" progression through the cell cycle# Bne nuclear protein in!ol!ed in the responses o" cells to TG+- is the proto-oncogene% c-Myc ,Cmic&C/ 'hich directly a""ects the e)pression o" genes har$oring Myc- $inding elements# $ac& to the top ,on-Receptor Serine/Threonine !inases The are se!eral serine/threonine &inases that "unction in signal transduction path'ays# The t'o more commonly &no'n are c%M$- dependent protein kinase "$!%# and protein kinase C "$!C## 4dditional serine/threonine &inases important "or signal transduction are the mitogen acti1ated protein kinases "M%$ kinases## $rotein !inase C "$!C# PKC 'as originally identi"ied as a serine/threonine &inase that 'as ma)imally acti!e in the presence o" diacylglycerols ,-4G/ and calcium ion# It is no' &no'n that there are at least ten proteins o" the PKC "amily# .ach o" these en*ymes e)hi$its speci"ic patterns o" tissue e)pression and acti!ation $y lipid and calcium# PKCs are in!ol!ed in the signal transduction path'ays initiated $y certain hormones% gro'th "actors and neurotransmitters# The phosphorylation o" !arious proteins% $y PKC% can lead to either increased or decreased acti!ity# B" particular importance is the phosphorylation o" the .G+ receptor $y PKC 'hich do'n-regulates the tyrosine &inase acti!ity o" the receptor# This e""ecti!ely limits the length o" the cellular responses initiated through the .G+ receptor# M%$ !inases M4P &inases 'ere identi"ied $y !irtue o" their acti!ation in response to gro'th "actor stimulation o" cells in culture% hence the name mitogen acti1ated protein kinases# M4P &inases are also called .RKs "or e'tracellular-signal regulated kinases# Bn the $asis o" in vitro su$strates the M4P &inases ha!e $een !ariously called microtu$ule associated protein-: &inase ,M4P-: &inase/% myelin $asic protein &inase ,MP &inase/% ri$osomal SD protein &inase ,RSK-&inase( i#e# a &inase that phosphorylates a &inase/ and .G+ receptor threonine &inase ,.RT &inase/# 4ll o" these proteins ha!e similar $iochemical properties% immuno- crossreacti!ities% amino acid se7uence and a$ility to in vitro phosphorylate similar su$strates# Ma)imal M4P &inase acti!ity re7uires that $oth tyrosine and threonine residues are phosphorylated# This indicates that M4P &inases act as s'itch &inases that transmits in"ormation o" increased intracellular tyrosine phosphorylation to that o" serine/threonine phosphorylation# 4lthough M4P &inase acti!ation 'as "irst o$ser!ed in response to acti!ation o" the .G+% P-G+% NG+ and insulin receptors% other cellular stimuli such as T cell acti!ation ,'hich signals through the >c& 2lick3 tyrosine &inase/% phor$ol esters ,that "unction through acti!ation o" PKC/% throm$in% $om$esin and $rady&inin ,that "unction through G-proteins/ as 'ell as N-methyl--- aspartate ,NM-4/ receptor acti!ation and electrical stimulation rapidly induce tyrosine phosphorylation o" M4P &inases# M4P &inases are% ho'e!er% not the direct su$strates "or RTKs nor receptor associated tyrosine &inases $ut are in "act acti!ated $y an additional class o" &inases termed M4P &inase &inases ,M4PK &inases/ and M4PK &inase &inases ,M4PKK &inases/# Bne o" the M4PK &inases has $een identi"ied as the proto-oncogenic serine/threonine &inase% Ra"# 9ltimate targets o" the M4P &inases are se!eral transcriptional regulators e#g# serum response "actor ,SR+/% and the proto-oncogenes +os% Myc and Eun as 'ell as mem$ers o" the steroid/thyroid hormone receptor super "amily o" proteins# $ac& to the top $hospholipases and $hospholipids in Signal Transduction Phospholipases and phospholipids are in!ol!ed in the processes o" transmitting ligand-receptor induced signals "rom the plasma mem$rane to intracellular proteins# The primary protein a""ected $y the acti!ation o" phospholipases is PKC 'hich is ma)imally acti!e in the presence o" calcium ion and -4G# The generation o" -4G occurs in response to agonist acti!ation o" !arious phospholipases# The principal mediators o" PKC acti!ity are receptors coupled to acti!ation o" phospholipase C- ,P>C-/# P>C- contains SH: domains that allo' it to interact 'ith tyrosine phosphorylated RTKs# This allo's P>C- to $e intimately associated 'ith the signal transduction comple)es o" the mem$rane as 'ell as mem$rane phospholipids that are its su$strates# 4cti!ation o" P>C- leads primarily to the hydrolysis o" mem$rane phosphatidylinositol $isphosphate ,PIP : / leading to an increase in intracellular -4G and inositol trisphosphate ,IP ; /# The released IP ; interacts 'ith intracellular mem$rane receptors leading to an increased release o" stored calcium ions# Together% the increased -4G and intracellular "ree calcium ion concentrations lead to increased acti!ity o" PKC# Recent e!idence indicates that phospholipases - and 4 : ,P>- and P>4 : / also are in!ol!ed in the sustained acti!ation o" PKC through their hydrolysis o" mem$rane phosphatidylcholine ,PC/# P>- action on PC leads to the release o" phosphatidic acid 'hich in turn is con!erted to -4G $y a speci"ic phosphatidic acid phosphomonoesterase# P>4 :
hydroly*es PC to yield "ree "atty acids and lysoPC $oth o" 'hich ha!e $een sho'n to potentiate the -4G mediated acti!ation o" PKC# B" medical signi"icance is the a$ility o" phor/ol ester tumor promoters to acti!ate PKC directly# This leads to ele!ated and unregulated acti!ation o" PKC and the conse7uent disruption in normal cellular gro'th and proli"eration control leading ultimately to neoplasia# $hosphatidylinositol--!inase "$+-!# PI-;K is tyrosine phosphorylated% and su$se7uently acti!ated% $y !arious RTKs and receptor-associated PTKs# PI-;K is a heterodimeric protein containing an ?1 &-a and 88@ &-a su$units# The p?1 su$unit contains SH: domains that interact 'ith acti!ated receptors or other receptor- associated PTKs and is itsel" su$se7uently tyrosine phosphorylated and acti!ated# The ?1 &-a su$unit is non-catalytic% ho'e!er% it does contain a domain homologous to GTPase acti!ating ,G4P/ proteins# It is the 88@ &-a su$unit that is en*ymatically acti!e# PI-;K% associates 'ith and is acti!ated $y% the P-G+% .G+% insulin% IG+-8% HG+ and NG+ receptors# PI- ;K phosphorylates !arious phosphatidylinositols at the ; position o" the inositol ring# This acti!ity generates additional su$strates "or P>C- allo'ing a cascade o" -4G and IP; to $e generated $y a single acti!ated RTK or other protein tyrosine &inases# $ac& to the top G-$rotein Coupled Receptors There are se!eral di""erent classi"ications o" receptors that couple signal transduction to G-proteins# These classes o" receptor are termed G- protein coupled receptors0 G$CRs# Aell o!er 8@@@ di""erent GPCRs ha!e $een cloned% most $eing orphan receptors ha!ing no as yet identi"ied ligand# Three di""erent classes o" GPCR are re!ie'ed( 1. GPCRs that modulate adenylate cyclase acti!ity# Bne class o" adenylate cyclase modulating receptors acti!ate the en*yme leading to the production o" c4MP as the second messenger# Receptors o" this class include the -adrenergic% glucagon and odorant molecule receptors# Increases in the production o" c4MP leads to an increase in the acti!ity o" PK4 in the case o" - adrenergic and glucagon receptors# In the case o" odorant molecule receptors the increase in c4MP leads to the acti!ation o" ion channels# In contrast to increased adenylate cyclase acti!ity% the - type adrenergic receptors are coupled to inhi$itory G-proteins that repress adenylate cyclase acti!ity upon receptor acti!ation# 2. GPCRs that acti!ate P>C- leading to hydrolysis o" polyphosphoinositides ,e#g# PIP : / generating the second messengers% diacylglycerol ,-4G/ and inositoltrisphosphate ,IP ; /# This class o" receptors includes the angiotensin% $rady&inin and !asopressin receptors# . 4 no!el class o" GPCRs are the photoreceptors# This class is coupled to a G-protein termed transducin that acti!ates a phosphodiesterase 'hich leads to a decrease in the le!el o" cGMP# The drop in cGMP then results in the closing o" a Na F /Ca :F channel leading to hyperpolari*ation o" the cell# See the Role o" =itamin 4 in =ision "or more details# $ac& to the top G-$rotein Regulators The acti!ity o" G-proteins 'ith respect to GTP hydrolysis is regulated $y a "amily o" proteins termed GT$ase acti1ating proteins0 G%$s# The proto- oncogenic protein% Ras% is a G-protein in!ol!ed in the genesis o" numerous "orms o" cancer ,'hen the protein sustains speci"ic mutations/# B" particular clinical signi"icance is the "act that oncogenic acti!ation o" Ras occurs 'ith higher "re7uency than any other gene in the de!elopment o" colo-rectal cancers# Regulation o" Ras GTPase acti!ity is controlled $y rasG%$# There are se!eral other G4P proteins $esides rasG4P that are important in signal transduction# There are t'o clinically important proteins o" the G4P "amily o" proteins# Bne is the gene product o" the neuro"i$romatosis type-8 ,N+8/ suscepti$ility locus# The N+8 gene is a tumor suppressor gene and the protein encoded is called neurofi/romin# The second is the protein encoded $y the CR locus ,/reak point cluster region gene/# The CR locus is rearranged in the PhiladelphiaF chromosome ,Ph F / o$ser!ed 'ith high "re7uency in chronic myelogenous leu&emias ,CM>s/ and acute lymphocytic leu&emias ,4>>s/# $ac& to the top +ntracellular )ormone Receptors Hormone receptors are proteins that e""ecti!ely $ypass all o" the signal transduction path'ays descri$ed thus "ar $y residing 'ithin the cytoplasm# 4dditionally% all o" the hormone receptors are $i-"unctional# They are capa$le o" $inding hormone as 'ell as directly acti!ating gene transcription# The steroid/thyroid hormone receptor super"amily ,e#g# glucocorticoid% !itamin -% retinoic acid and thyroid hormone receptors/ is a class o" proteins that reside in the cytoplasm and $ind the lipophilic steroid/thyroid hormones# These hormones are capa$le o" "reely penetrating the hydropho$ic plasma mem$rane# 9pon $inding ligand the hormone- receptor comple) translocates to the nucleus and $ind to speci"ic -N4 se7uences termed hormone response elements ")R&s## The $inding o" the comple) to an HR. results in altered transcription rates o" the associated gene# $ac& to the top $hosphatases in Signal Transduction Su$stantial e!idence lin&s $oth tyrosine and serine/threonine phosphorylation 'ith increased cellular gro'th% proli"eration and di""erentiation# Remo!al o" the incorporated phosphates must $e a necessary e!ent in order to turn o"" the proli"erati!e signals# This suggests that phosphatases may "unction as anti-oncogenes or gro'th suppressor genes# The loss o" a "unctional phosphatase in!ol!ed in regulating gro'th promoting signals could lead to neoplasia# Ho'e!er% e)amples are &no'n 'here dephosphorylation is re7uired "or promotion o" cell gro'th# This is particularly true o" speciali*ed &inases that are directly in!ol!ed in regulating cell cycle progression# There"ore% it is di""icult to en!ision all phosphatases as $eing tumor suppressor genes# There are t'o $road classes o" protein tyrosine phosphatases "$T$s## Bne class are transmem$rane en*ymes 'hich contain the phosphatase acti!ity domain in the intracellular portion o" the protein# The other are intracellularly locali*ed en*ymes# The "irst transmem$rane PTP characteri*ed 'as the leukocyte common antigen protein0 C234# This protein 'as sho'n to ha!e homology to the intracellular PTP% PTP8# There are at least si) su$-classes o" the transmem$rane PTPs# The clearest studies o" a role "or transmem$rane PTPs in signal transduction ha!e in!ol!ed the C-01 protein# These studies ha!e sho'n that C-01 is in!ol!ed in the regulation o" the tyrosine &inase acti!ity o" lc& in T cells# 4s indicated a$o!e >c& is associated 'ith T cell antigens C-0 and C-? generating a split-RTK in!ol!ed in T cell acti!ation# It is suspected that C-01 dephosphorylates a regulatory tyrosine phosphorylation site in the C-terminus o" >c&% there$y% increasing the acti!ity o" >c& to'ards its su$strate,s/# The second class o" PTPs are the intracellular proteins# The C-terminal residues o" most i" not all intracellular PTPs are !ery hydropho$ic and suggest these sites are mem$rane attachment domains o" these proteins# Bne role o" intracellular PTPs is in the maturation o" Xenopus oocytes in response to hormone# B!er e)pression o" PTP-8 in oocytes resulted in a mar&ed retardation in the rate o" insulin- and progesterone-induced maturation# These results suggest a role "or PTP-8 in countering the signals leading to cellular acti!ation# The a$o!e o$ser!ation as 'ell as se!eral others ha!e demonstrated a lin& $et'een insulin "unction and PTP-8# PTP-8 directly interacts 'ith the insulin receptor and remo!es the tyrosine phosphates incorporated $y autophosphorylation in response to insulin $inding% there$y% negati!ely a""ecting the acti!ity o" the insulin receptor# Recently the PTP-8 gene 'as disrupted in mice $y targeted deletion# Mice lac&ing a "unctional PTP-8 gene e)hi$it increased insulin sensiti!ity as 'ell as resistance to o$esity induced $y a high "at diet# 4s 'ith the transmem$rane PTPs little is &no'n a$out the regulation o" the acti!ity o" the intracellular PTPs# T'o intracellular PTPs ,PTP-8C and PTP-8-/ ha!e $een sho'n to contain SH: domains# These SH: domains allo' these PTPs to directly interact 'ith tyrosine phosphorylated RTKs and PTKs% there$y% dephosphorylating tyrosines in these proteins# +ollo'ing receptor stimulation o" signal transduction e!ents% the SH: containing PTPs are directed to se!eral o" the RTKs and/or PTKs 'ith the net e""ect $eing a termination o" the signaling e!ents $y tyrosine dephosphorylation Bther phosphatases that recogni*e serine and/or threonine phosphorylated proteins also e)ist in cells# These are re"erred to as protein serine phosphatases "$S$s## 4t least 81 distinct PSPs ha!e $een identi"ied# The type :4 PSPs e)hi$it selecti!e su$strate speci"icity to'ards PKC phosphorylated proteins< in particular serine and threonine phosphorylated receptors# Type :4 PSPs are more e""ecti!e than other PSPs in dephosphorylating RSKs% proteins that are in!ol!ed in signaling cascades $y phosphorylating ri$osomal SD protein ,see a$o!e/# Ho'e!er% a type 8 PSP is re7uired to dephosphorylate SD itsel"# The type :4 PSPs ha!e : su$units ,a regulatory and a catalytic/ $oth o" 'hich can associate 'ith one o" the tumor antigens o" the -N4 tumor !irus% polyoma# Trans"ormation $y -N4 tumor !iruses such as polyoma appears to $e mediated $y the "ormation o" a signal transduction unit consisting o" a !irally encoded T antigen and se!eral host encoded proteins# Se!eral host proteins are tyrosine &inases o" the src "amily# Polyoma middle T antigen also can $ind to PI-;K# The association o" type :4 PSPs in these comple)es may lead to dephosphorylation o" regulatory serine/threonine phosphorylated sites resulting in increased signal transduction and su$se7uent cellular proli"eration# $ac& to the top Return to Medical iochemistry Page Michael W. King, Ph.D / I !chool o" Medicine / m#ing$medicine.indstate.edu >ast modi"ied( Tuesday0 12-%ug-255 2565467 &ST
Download pdf Solution Manual For Molecular Cell Biology 8Th Edition Harvey Lodish Arnold Berk Chris A Kaiser Monty Krieger Anthony Bretscher Hidde Ploegh Angelika Amon Kelsey C Martin 33 online ebook full chapter