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CONTACT INFORMATION: LUISA IRUELA-ARISPE BSRB/ORH 445 PHONE# 310 - 794-5763 arispe@mbi.ucla.edu

Cell-Matrix Interactions Lecture 2 January 8th, 2008. CONTACT INFORMATION: LUISA IRUELA-ARISPE BSRB/ORH 445 PHONE# 310 - 794-5763 arispe@mbi.ucla.edu. CELL-MATRIX CONTACTS ARE ESSENTIAL FOR NORMAL CELL PHYSIOLOGY. Cells bind to matrix proteins via specific cell surface receptors.

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CONTACT INFORMATION: LUISA IRUELA-ARISPE BSRB/ORH 445 PHONE# 310 - 794-5763 arispe@mbi.ucla.edu

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  1. Cell-Matrix Interactions Lecture 2 January 8th, 2008 CONTACT INFORMATION: LUISA IRUELA-ARISPE BSRB/ORH 445 PHONE# 310 - 794-5763 arispe@mbi.ucla.edu

  2. CELL-MATRIX CONTACTS ARE ESSENTIAL FOR NORMAL CELL PHYSIOLOGY Cells bind to matrix proteins via specific cell surface receptors. Integrins comprise the larger family of ECM receptors. These heterodimeric proteins are ubiquitously expressed. The number, activation status and types of integrins expressed at the cell surface regulates the interaction with the substrate.

  3. Extracellular matrix integrin Src cytosol Grb2 Sos Raf MAP kinase cascade Actin filament actinin nucleus Binding to ECM intiates integrin signaling and engagement of the cytoskeleton 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.

  4. Dimeric associations between alpha and beta integrins 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 binding to ligands can be mediated by the tripeptide RGD

  6. AT THE CELL SURFACE INTEGRINS CAN BE EITHER ACTIVE (OPEN) OR INACTIVE (BENT) Highly bent integrin conformation has low affinity for biological ligands

  7. 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.

  8. PAPER 2 Question being addressed: How does ligand binding alter integrin conformation?

  9. ELECTRON MICROGRAPHS AND • REPRESENTATIVE PROJECTION AVERAGES • OR NEGATIVELY STAINED • avß3 • 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

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

  11. (50, 100, and 150nM) Clasped Unclasped 1mM Ca and Mg Effect of divalent cations on the activation status of integrins evaluated by surface plasmon resonance 1mM Mn (50, 100, and 150nM) 1mM Ca and Mg 1mM Mn Takagi et al., 2002

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

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

  14. What is the biological relevance of the status of integrin activation? It allows for dynamic interactions with the substrate during migration in a manner that can be controlled either from the inside or outside of the cell and independently in different regions of the cell.

  15. Paper 3 Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD Dolganov G, Glick A, Sheppard D. Loss of integrin alpha(v)beta6-mediated TGF-beta Activation causes Mmp12-dependent emphysema. Nature. 2003 Mar 13;422(6928):169-73 Question being addressed: What is the biological contribution of integrin beta6? Important background: Alphav beta6 integrin has been shown to activate TGF-beta TGF-beta plays an important function in lung homeostasis

  16. Hinge region Heparin-binding site Proteinase cleavage site Structure of latent TGF-beta Proteinase-sensitive region LTBP-1 ECM-binding sites Latent-TGF-b Binding site ECM-binding sites Activation of TGF-beta by integrins Active TGF-b Cell LAP LAP Hinge region LTBP ECM

  17. Spontaneous, progressive pulmonary emphysema (enlarged alveoli) in Itgb6 null mice Increased linear intercepts of alveolar septae

  18. Transgenic expression of human ITGB6 or ITGB6 reduces Mmp12 expression normalizes macrophage appearance and prevents the development of airspace enlargement in Itgb6 null mice FL 777T

  19. Transgenic expression of Tgfb Cys-Ser normalizes alveolar macrophage appearance and reduces Mmp12 expression in Itgb6 mice 223,225

  20. Deletion of Mmp12 prevents spontaneous emphysema in Itgb6 null mice but does not affect inflammation

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