CONTACT INFORMATION: LUISA IRUELA-ARISPE MBI/BOYER HALL 559 PHONE# 310 - 794-5763

1. CELL-MATRIX INTERACTIONS Lecture 3 January 13th, 2006 CONTACT INFORMATION: LUISA IRUELA-ARISPE MBI/BOYER HALL 559 PHONE# 310 - 794-5763 arispe@mbi.ucla.edu

2. Extracellular matrix integrin Src cytosol Grb2 Sos Raf MAP kinase cascade Actin filament actinin nucleus Signaling Through Integrins Extracellularly: b subunit binds to specific matrix proteins Intracellularly: • subunit binds to talin which interacts with actin and paxillin. Src phosphorylates FAK, which becomes linked to Grb2-Sos, which activates Ras, which sends signals along the MAP kinase pathway.

3. STRUCTURE OF INTEGRINS (EXTRACELLULAR DOMAINS) Highly bent integrin conformation has low affinity for biological ligands

4. Leukocyte-specific receptors Collagen Receptors aIIb a2 a10 b2 a1 a11 b3 a5 aL aD b1 a9 b5 aM av aX a4 b6 a8 b8 a7 a3 a6 b7 RGD Receptors Laminin Receptors aE b4

5. Integrins can also mediate Cell-cell interactions aIIbb3 integrin • During clotting, platelets aggregate because their integrin aIIbb3 binds to a molecule of fibrinogen. • Presence of RGD peptides can inhibit blood clot formation by competing with fibrinogen molecules for the RGD binding sites on the integrins.

6. There are Multiple Integrins

7. INTEGRINS EXISTS IN MUTIPLE THREE DIMENSIONAL STATES Takagi et al., 2002

8. LIGAND BINDING • ALTERS INTEGRIN • CONFORMATION BY • INSIDE-OUT-SIGNALING • Addition of high affinity • ligand mimetic peptide • or Mn results in a • switchblade-like Opening to • an extended structure Takagi et al., 2002

9. QUATERNARY STRUCTURAL REARRANGEMENTS IN INTEGRIN ACTIVATION Takagi et al., 2002

10. Dynamic interactions of integrins with the substrate during cell migration

11. ß1 Integrin Subfamily KO phenotype a1 Increased collagen sysnthesis a2 Early embryonic lethal a3 Impaired renal and lung dev. a4 Impaired cardiac development a5 Impaired extraembryonic and embryonic vascular development a6 ß4 Severe skin blistering a7 Muscular dystrophy a8 Small or absent kidneys a9 bilateral chylothorax a10 Not reported a11 Not reported ß1 ? Early gastrulation defect

12. ß2 Integrin Subfamily KO phenotype aL Impaired tumor rejection impaired leukocyte recruitment aM Impaired phagocytosis and PMN apoptosis obesity aX Not reported aD Not reported ß2 Impaired leukocyte recruitment and skin infections

13. av Integrin Subfamily KO phenotype ß1 Unknown ß3 Defective platelet aggregation, osteosclerosis ß5 Normal ß6 Lung, skin inflammation, impaired lung fibrosis ß8 Not reported aIIb av Defective development of CNS and GI blood vessels, cleft palate

14. INTEGRIN SIGNALING OCCURS (for the most part) THROUGH THE BETA CHAIN

15. Multiple proteins have been shown to interact with the cytoplasmic domain of integrins

16. Integrin signaling is context-dependent

17. SIGNALING BY INTEGRINS HAVE BEEN SHOWN TO MEDIATE: 1- TRACTIONAL FORCES 2- MIGRATION 3- REGULATION OF APOPTOSIS 4- CELL SURVIVAL 5- MODULATE SIGNALS FROM GROWTH FACTORS

18. DOWNSTREAM SIGNALING MEDIATED BY INTEGRINS

19. CONTRIBUTION OF INSIDE-OUT SIGNALING TO INTEGRIN FUNCTION INSIDE-OUT SIGNALING

20. FOCAL ADHESION KINASE - REGULATION OF DETACHMENT