integrins

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I t ri tr t r

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Interactions between integrins &

the cytoskeleton

F oc al a dhes ion s

He mid es mo s om e

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Interactions betweenintegrins & the cytoskeleton

Focal adhesionsloc al ize d poin ts of atta chme nt betwee n c ell surfa ce inte gr ins a nd the extra cellular matr ix

inte gr in mo lecules c lustere d

se veral linker pr ote ins

bundles of actin microfilaments

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He mid es mo s om es

poin t of atta chme nt betwee n c ell surfa ce inte gr in mo lecules of ep ithel ial cells a nd the basal lamin a

Inte gr in mo lecules a nc hore d via linker pr ote ins to intermediate filaments of the cytos kelet on

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I t r ti t

i t ri t t l t

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Inte gr in ind uce d effe cts on the cytos kelet on

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Inte gr ins are at the Cr ossr oa ds of Comm unic at ionBetwee n the Extra cellular a nd In tra cellular Envi r onm e nts

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Function of integrins

Integrins have two main functions

Atta chme nt of the cell to the ECM

Sign al tra ns duction fr om the ECM to the cell

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Function of integrins

Re gulate cell mov e me nt

Re gulate cell atta chme nt

Intera ct with intra cellular s ign al ing pathways

e .g. MAPK a ctivat ion s causes inte gr incluster ing

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Function of integrinsCa n a ctivate intra cellular s ign al ing pathways

Anc hora ge- depe nd e nt gr owthCells must be atta che d to a su bstratu m to

gr ow otherw ise ap optos is occ urs

inte gr in c luster ing re cru its kinases (e .g.F (f oc al)AK) to f oc al a dhes ion s via a dapter pr ote ins (e .g. pax illin)Ca nc er cells a nc hora ge ind epe nd e nt gr owthcon ta in con st itut ively a ctivate d F AK

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Attachment of cell to the ECM

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Attachment of cell to the ECM

s ign als ar is ing fr om re cept ors f or s oluble gr owth factors like VEG F , EG F , a nd m a ny others

he atta chme nt of the cell ta kes pla ce thr ough f or mat ion o f cell a dhes ioncom plexes

ma ny cytoplas mic pr ote ins su ch as tal in, vinc ulin, pax illin, a nd alpha-a ctinin. These a ct by re gulat ing kinases su ch as F AK(f oc al a dhes ion kin ase ) a nd S r c kin ase

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S ignal transduction

The s ign als the cell re ce ives thr ough the inte gr in c a n ha ve relat ion to:

cell gr owthcell divis ioncell sur vival

cellular differe ntiat ionap optos is (pr og ra mm e d c ell death )

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S ignal transduction

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Inte gr ins a nd Sign al Tra ns duction

F oc al a dhes ion kin ase (F AK) b e com es tyr os ine ph osph orylate d d ur ing in te gr in -me diate d c ell a dhes ion.

F AK is a non -re cept or tyr os ine kinase intera cting with C- sr c, PI3 -K,Rho

GTP ase, Gr b-2 a nd p1 30 CAS .

F AK-ge nerate d s ign al ing i s invo lve d in c ell sur vival a nd esse ntial f or de velopme nt

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Connec ting t e c tin cy toske le ton to t e ex tr ce ll l r tri x y f oca l con tac ts

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Connec ting t e ac tin cy toske le ton to t e ex tr ace ll la r a tri x y f oca l

con tac ts

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Cr oss tal k b etwee n in te gr ins a nd g r owth factor re cept ors

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Effects of IntegrinSignaling

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Integrins protect cellsagainst anoikis

Anoiki s : Ind uction o f ap optos is by loss of inte gr in-me diate d a dhes ion

Inte gr ins a nd F AK a ctivate PI3Kind epe nd e nt of RTK s . Akt will tur n onwhich de gra des a nd in a ctivates p27 ,

inhibit Ba d, et c.

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Integrins protect cells

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Integrins protect cells

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L eu koc ytes a nd in te gr in s ign al ing

Inte gr ins are domin a nt family of cell a dhes ion re cept ors invo lve d in leu koc yte intera ction s with e ndo thel ium a nd ECM .

Inte gr in s ign al ing pathways - mig rat ion , sprea ding , a ctivat ion o f the resp irat ory

burst, com ple me nt binding , cell a dhes ion , cytokin es a nd c he mokin e express ion , a ndap optos is .

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L eu koc ytes a nd in te gr in s ign al ing

Dur ing in flamm at ion , neutr oph ils r oll alongthe e ndo thel ial wall

F AK, re cru its s ign al ing pr ote ins- PI3 -K a nds ign al ing

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i t gr i s e ia te leuk cy te -e t e lia l ce ll a hei son n ea r s ite s of inf ec tion

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D isintegrins : A family of Cyste ine r ich pept ide with RGDmo tif Thr ough RGD mo tifs Dis inte gr ins bind tointe gr ins inhibiting in te gr in relate dfunc tion sInte gr in in hibitory pr ote ins were f irst dis cov ere d in s na ke ve nom

In s na ke ve nom di s inte gr ins pept ides ha dother a ctive seque nc es like KGD ,MVD,ML D,VGD ,ECD ,or MDG in

inte gr in mo tifs

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Conc lus ion s

In F AK d ef icie nt mic e de velopme ntal defe ct ass oci ate d with impa ir me nt of cell mig rat ion a nd e nha nc e me nt of cell

a dhes ion.Inte gr in m e diate d c -Ju n kin ase a ctivat ionis depe nd e nt on F AK a nd i s invo lve d incell cycle pr og ress ion a nd c ell sprea dinga nd c ell sur vival .

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Conc lus ion s Ac tivat ion o f p38 MAPK b y inte gr ins re gulate co llage n g e ne express ion a nd c ell mo tility.Inte gr in- me diate d c ell a dhes ion als ost imulates RHO family me mb ers inc ludingRhoA, Ra c1, a nd CDC42.Dis inte gr ins ,l iga nd s of IIb3 i s a pote nt

inhibitors of platelet a gg re gat ion a nd tumo r cell metastas is, a nd liga nd s of 5 1 a nd

v3 in hibits a ngiog e nes is a nd ind uce

ap optos is in c ells .

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integrins

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