Polyamine-dependent activation of Rac1 is stimulated by focal adhesion-mediated Tiam1 activation.
Integrin receptors cluster on the cell surface and bind to extra cellular matrix (ECM) proteins triggering the formation of focal contacts and the activation of various signal transduction pathways that affect the morphology, motility, gene expression and survival of adherent cells. Polyamine depletion prevents the increase in autophosphorylation of focal adhesion kinase (FAK) and Src during attachment. Rac activity also shows a steady decline, and its upstream guanine nucleotide exchange factor (GEF), Tiam1 also shows a reduction in total protein level when cells are depleted of polyamines. When Tiam1 and Rac1 interaction was inhibited by NSC-23766, there was not only a decrease in Rac1 activity as expected but also a decrease in FAK auto-phosphorylation. Inhibition of Src activity by PP2 also reduced FAK autophosphorylation, which implies that Src modulates FAK autophosphorylation. From the data obtained in this study we conclude that FAK and Src are rapidly activated upon fibronectin mediated signaling leading to Tiam1-mediated Rac1 activation and that intracellular polyamines influence the signaling strength by modulating interaction of Src with Tiam1 using focal adhesion kinase as a scaffolding site.
Elias
Bertha C
BC
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Bhattacharya
Sujoy
S
Ray
Ramesh M
RM
Johnson
Leonard R
LR
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D009842:Oligopeptides; D011073:Polyamines; C046617:arginyl-glycyl-aspartyl-serine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein
J Biol Chem. 1997 Dec 26;272(52):33105-10
9407095
Am J Physiol Gastrointest Liver Physiol. 2007 Apr;292(4):G983-95
17170026
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7618-23
15128949
Mol Cell Biol. 2002 Apr;22(8):2427-40
11909938
Am J Physiol. 1984 Jun;246(6 Pt 1):G649-53
6430095
Gastroenterology. 1993 Jan;104(1):65-74
8093445
Neoplasia. 2008 May;10(5):408-17
18472958
Bioorg Med Chem Lett. 2001 Jun 18;11(12):1613-7
11412992
Exp Cell Res. 1992 Oct;202(2):370-5
1397089
Prog Biophys Mol Biol. 2003 Jan;81(1):1-44
12475568
Nat Rev Cancer. 2004 Oct;4(10):781-92
15510159
Cancer Res. 2005 Feb 15;65(4):1335-42
15735019
Am J Physiol. 1990 Jan;258(1 Pt 1):G78-85
1689120
Am J Physiol. 1984 Nov;247(5 Pt 1):G553-7
6437251
Am J Physiol. 1983 Nov;245(5 Pt 1):G656-60
6638190
Am J Pathol. 2000 Mar;156(3):985-96
10702414
Nat Rev Drug Discov. 2007 May;6(5):373-90
17464296
Am J Physiol. 1990 Jun;258(6 Pt 1):G942-50
1694401
J Biol Chem. 1997 Apr 18;272(16):10751-5
9099726
Biochem Biophys Res Commun. 1996 Nov 21;228(3):662-8
8941336
Gut. 2003 Mar;52(3):439-51
12584232
Trends Cell Biol. 2005 Aug;15(8):399-403
16005629
Mol Cell Biol. 1996 Oct;16(10):5623-33
8816475
FEBS Lett. 2003 Jul 3;546(1):11-6
12829230
Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G1137-47
16798728
Biochem J. 2006 Aug 1;397(3):437-47
16669788
J Biol Chem. 2003 Sep 5;278(36):34339-46
12810717
EMBO J. 1999 Feb 1;18(3):578-85
9927417
J Biol Chem. 2003 Apr 11;278(15):13039-46
12574162
Am J Physiol Cell Physiol. 2001 Aug;281(2):C475-85
11443046
Cell Signal. 2007 Dec;19(12):2519-27
17825525
Nat Cell Biol. 2002 Aug;4(8):621-5
12134164
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7188-93
18480266
Cell Mol Life Sci. 2006 Dec;63(23):2871-9
17109063
J Biol Chem. 2007 Jan 5;282(1):14-28
17088251
Cell Motil Cytoskeleton. 2007 Mar;64(3):143-56
17183546
Curr Opin Gastroenterol. 2006 Mar;22(2):85-9
16462161
Exp Cell Res. 2009 Apr 1;315(6):1008-14
19331812
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13298-302
14593208