19 Tyrosine Kinase 2009

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PROTEIN TYROSINE KINASES (PTK) SUPERFAMILY

5 Classes of PTK superfamily

AGC group - PKA, PKG, PKC, Rac, G-protein kiasesCaMK group - kinases regulated by Ca++/CaM

CMGC group - cyclin-dependent kinases ERK, MAP, Casein kinasePTK group - conentional protein tyrosine kinases !rc, Abl, "ak, P#G", $R

%PK - ot&er protein kinases

Physiological Function - play an important role in

'( Gro)t& Control

*( Cell-cell recognition

( Cell cycle control

( $une responses

.( #eelopent and dierentiation

Tyrosine kinases and associated genes and protein &ae been iplicated in deelopental deectsand cancer( E0cessie actiation o receptor tyrosine kinase can lead to uncontrolled gro)t& and

alignant transoration(

Many deectie or iral ors o tyrosine kinase and associated proteins are oncogenes1 -src,abl, erb2

General comments

$noled in p&osp&orylating speciic Tyr residues in arious target proteins( T&is is a key eent

o intracellular signal transduction, particularly early steps

Most tyrosine kinase Receptors e0ist as inactie onoers in t&e ebranes( 3igand-inducedreceptor dieri4ation induces receptor autop&osp&orylation

P&osp&o-Tyr residues in t&e cytoplasic doain o receptor act as docking sites t&at bind

cytoplasic signaling olecules

5%TE1 T&ere is oten cross-talk bet)een tyrosine kinase-induced pat&)ays and ot&er signalingpat&)ays


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RECEPTOR TYROSINE KINASES (RTK)

General Bac!ro"n#

'( Rtk are transebrane glycoproteins( T&ey are actiated by binding o t&eir cognate ligandsand transduce t&e e0tracellular signal to t&e cytoplas by p&osp&orylating Tyr residues on '6 t&e

receptors t&eseles 7autop&osp&orylation6 and *6 do)nstrea signaling proteins

*( RTK can actiate a ariety o signaling pat&)ays t&at are inoled in cell prolieration,

dierentiation, igration and etabolic c&anges

( RTK aily includes receptors or insulin and any ot&er gro)t& actors 7e(g( EG", "G",

P#G", 8EG" and 5G"6

A( 5on-receptor tyrosine kinases 75RTK6 - includes !rc, 9anus kinases 79ak6, Abl and ot&ers(

T&ey are integral coponents o t&e signaling cascade triggered by '6 RTK: *6 ot&er cell surace

receptors suc& as GPCR: 6 receptors o t&e iune syste(

Cell"lar s$!nal$n!

'( Play iportant roles in ebryonic deelopent, etabolis and iune syste unction

*( 8asculogenesis - re;uires 8EG" ad K#R, t&e RTK t&roug& )&ic& it acts( Angiogenesis - reuires 8EG" receptor "lt' and angiopoietin ', a ligand or t&e RTK Tie*

a( $nsulin - is a eber o t&e RTK aily : insulin actiates $R! proteins

Non%rece&tor t'ros$ne $nases or NRTK ( memers* lar!est +am$l' $s Src ,$t- . memers)

'( !rc - inoled in itogenesis, T and 2 cell actiation, cytoskeleton restructuring

*( !rc &as been iplicated in &uan carcinoas suc& as breast, lung, colon cancer( Many in io substrates &ae been identiied or !rc 7e(g( P#G", EG", "ak, p'ap?ap?< is actiated

by 3ck 7p&osp&orylation6 and t&e is inoled in do)nstrea signaling eents t&at ediate t&e

transcriptional actiation o cytokine genes

ii( 2 cell receptor actiation actiates lyn 7src eber6 )&ic& recruits and p&osp&orylates !yk a

>AP?


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Prote$n Str"ct"re o+ RTK an# NRTK

RTK

Conta$n / ma0or #oma$ns

'( E0tracellular portion - binds polypeptide ligands

*( Transebrane &eli0

( Cytoplasic portion - possesses Tyr kinase catalytic actiity

Ma0or$t' o+ RTK e1$st as a s$n!le &ol'&e&t$#e an# are monomer$c $n t-e asence o+ l$!an#2

Most polypeptides ligands or RTK are soluble

E1tracell"lar #oma$n o+ RTK conta$ns a ,$#e arra' o+ #$screte !lo"lar #oma$ns7e(g(

iunoglubulin-like, ibronectin type $$$, Cys-ric& doains and EG"-like6

C'to&lasm$c #oma$ns % cons$st o+ a 0"1tamemrane re!$on3 +ollo,e# ' t-e t'ros$ne $nase

catal't$c #oma$n an# a COO4%term$nal re!$on2 In a##$t$on to TK $nsert3 t-ere are re!$ons

t-at conta$n T'r res$#"es t-at are a"to&-os&-or'late# a+ter l$!an# $n#$n!


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T'ros$ne A"to&-os&-or'lat$on

I2 Act$5at$on o+ RTK re6"$res7

'6 En&anceent o intrinsic catalytic actiity and*6 Creation o binding sites to recruit do)nstrea signaling proteins( 2ot& o t&ese processes

occur by autop&osp&orylation on Tyr residues, due to ligand-ediated oligoeri4ation

II2 A"to&-os&-or'lat$on o+ T'r $n t-e act$5at$on loo& ,$t-$n t-e $nase #oma$n res"lts $n7

'6 stiulation o kinase actiity and

*6 generation o docking sites in t&e @u0taebrane, kinase insert and C%% regions ia Tyr

p&osp&orylation or odular doains t&at recogni4e speciic p&osp&o-Tyr se;uences

All RTK contain bet)een '- Tyr in t&e kinase actiation loop( P&osp&orylation o t&ese Tyr is

iportant or stiulation o catalytic actiity and biological unction or a nuber o RTK

5%TE1 auto-p&osp&orylation o actiation loop Tyr occurs ia a trans-ec&anis 7i(e( bet)een

receptors6

III2 8$mer$9at$on

'( 3igand-induced oligoeri4ation o RTK is t&e ec&anis t&at triggers or induces tyrosineautop&osp&orylation( 3igand binding stabili4es a dieric coniguration o t&e e0treacellular

doains o RTK

*( 3igand binding to t&e e0tracellular doain ediates t&e non-coalent oligoeri4ation o

onoeric receptors or induces rearrangeent in &eterotetraeric receptors 7e(g( insulin

receptor6, acilitating Tyr autop&osp&orylation

( Typically, RTK dieri4ation is probably suicient or transducing t&e biological signal(E0ceptions include t&e Ep& receptors, )&ere a tetraeric or is re;uired to produce t&e ull

range o biological responses(

:2 8o,nre!"lat$on o+ RTK

%ccurs by receptor-ediated endocytosis, ubi;uitin-directed proteolysis and protein tyrosinep&osp&atases 7PTP6


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S$!n$+$cance o+ t-e P-os&-or'lat$on o+ Rece&tor T'ros$ne Res$#"es

T-e T'r%P Gro"&s can t-en act as a#a&ters3 sca++ol#s or &lat+orms +or ot-er s$!nal$n!

molec"les $n t-e c'to&lasm


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NRTK

2 Lac rece&tor%l$e +eat"res7e0tracellular binding doain and transebrane spanning

region6 and ost are locali4ed in t&e cytoplas

a( !oe 5RTK are anc&ored to t&e cell ebrane ia aino terinal odiication suc& as

yristolation and palitoylation

;2 Possess TK #oma$n an# #oma$ns t-at me#$ate &rote$n%&rote$n3 &rote$n%l$&$# an# &rote$n%

8NA $nteract$ons2 Most common #oma$ns $n NRTK are t-e Src -omolo!' ; (S4;) an# Src

-omolo!' / (S4/) #oma$ns

a( !* - binds p&ospo&o-Tyr residues in a se;uence-speciic anner and

b( ! - binds proline-containing se;uences capable o oring polyproline type $$ &eli0

c( 5RKT t&at lack !* and ! doains contain sub-aily speciic doains used or protein-

protein interactions(

d( 9ak aily &ae speciic doains t&at target t&e to t&e cytoplasic portion o cytokinereceptors(

e( "ak possesses an integrin-binding doain and a ocal ad&esion -binding doain(

( 2tk/Tec subaily &ae t&e pleckstrin &oology 7P6 doain - t&ese bind to Ptd$ns lipids t&at

&ae been p&osp&orylated at speciic positions on t&e &ead group(


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I2 Re!"lat$on o+ NRTK

'( Most coon ec&anis o regulation is Tyr p&osp&orylation( Generally, p&osp&orylation o

Tyr in actiation loop o 5RTK leads to an increase in en4yatic actiity(

*( Actiation loop p&osp&orylation occurs ia '6 trans-p&osp&orylation or *6 p&osp&orylation by

a dierent 5RTK( P&osp&orylation o Tyr outside o actiation loop can negatiely regulatedkinase actiity(

( PTP restore 5RTK to basal state and in soe cases, can negatiely regulate 5RTK actiity

II2 Se!"lat$on o+ Src

!rc contains '6 yristoylated 5* terinus *6 a stretc& o positiely c&arged residues t&at

interact )it& p&osp&olipid &ead groups 6 a s&ort region o lo) se;uence &oology 6 !*

doain .6 ! doain B6 Tyr kinase doain and ?6 s&oort C%%-terinal tail

III2 Src &ossesses ; $m&ortant re!"lator' T'r &-os&-or'lat$on s$tes

'( P&osp&orylation o Tyr-.*? in t&e C%%-terinal tail by t&e 5RTK Csk REPRE!!E!

kinase actiity(

a( -!rc, an oncogenic ariant o !rc, lacks t&e negatiely regulatory site Tyr-.*?( T&is leads toconstitutie actiity and uncontrolled gro)t& o aected cells

b( c-!rc - substitution o Tyr-.*? )it& P&e results in its actiation

*( !econd regulatory p&osp&orylation site is Tyr-'B, an autop&osp&orylation site in t&e

actiation loop( Ma0ial stiulation occurs )&en Tyr-'B is p&osp&orylated and Tyr-'B

P&e suppresses t&e transoring action o Tyr-.*? P&e utation

( !* and ! doains negatiely regulate !rc actiity( Mutation in !* and ! doainsactiate !rc(

( pTyr-.*? &as intraolecular interaction )it& !* doain( $ntraolecular interaction bet)een

! and segent linking !* doain )it& kinase )&ic& ors a s&ort polyproline type $$ &eli0

.( Mec&anis by )&ic& !rc kinase actiity is repressed is not by occlusion o t&e actie site by

s* or !: t&ese doains are located on t&e back side o t&e kinase doain, opposite t&e

catalytic clet( $ntraolecular interactions stabili4e t&e isalignent o residues critical or

catalytic actiity and restrict t&e relatie otion o t&e * kinase lobes to preent productie ATP

binding

A n"mer o+ t-at t-at $n# to Act$5ate# RTK an# $ts &ro#"cts are no,n as t-e Src4omolo!' 8oma$ns (or S4 8oma$ns)2

!rc 7!arcoa irus6 - represents a proto-oncogene t&at &as tyrosine kinase actiity( $t is a

prototypical odular signaling protein( Play key roles in cell orp&ology, otility, prolieration

and surial(

! #oains - t&ese are adapter proteins t&at odulate signaling by protein tyrosine kinase


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S&ec$+$c In+ormat$on ao"t t-e str"ct"ral #oma$ns o+ Src $nase +am$l' memers

Classiied as non-receptor tyrosine kinases 75RTK6

5RKT are integral coponents o signaling cascades triggered by RTK, ot&er cell suracereceptors and receptors o t&e iune syste( Play a a@or role in itogenesis, T- 73ck, >ap6

and 2-cell actiation 73yn, !yk, 2tk6 and cytoskeleton restructing

Play a@or role in spreading, ocal ad&esion oration/disassebly, igration, cell cycle

progression, apoptosis, dierentiation, gene transer

Certain 5RTK interact )it& RTK and GPCR


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Src an# $ts +am$l' memers conta$n common molec"lar mot$+s (see elo,)

2 S4: % memrane local$9at$on s$!nal

'. aino acid se;uence t&at contains t&e signal or lipid odiication( Gly* is re;uired or

addition o yristic acid 7e0cept or "rk6

;3 Un$6"e 8oma$n

#istinct or eac& aily eber

May acilitate interactions )it& speciic receptor

$n !rc and 3yck, !er/T&r p&osp&orylations occur, usually during itosis

/2 S4/ % Beta%Barrel

All contain propro as a core: -nteracts )it& Proline-ric& peptides

Regulates intra- and intraoecular interactions

$portant in en4ye actiity, cellular location

Recruits substrates 7acts as adapter or scaold6

:2 S4; % P-os&-o%T'r re!$on

All bind s&ort, contiguous se;uences containing p&osp&orylated Tyr: bind peptides )it&

consensus se;uence Ptyr-Met/8al--Met( $noled in locali4ation, recruitent o binding

partners


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Belo, $s an e1am&le o+ $nteract$on o+ S4; an# S4/ #oma$ns ,$t- ot-er s$!nal$n! molec"les


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T'ros$ne K$nase%L$ne# Rece&tors

Protot'&e % $nteract$on o+ c'to$nes ,$t- t-e$r rece&tors


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19 Tyrosine Kinase 2009

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