It is 40 years since the first member of what came to be known as the matrix metalloproteinase (MMP) family was described. Structural, molecular and biochemical approaches have subsequently contributed to piecing together the puzzle of how MMPs work, and how they contribute to various disease processes.

Matrix metalloproteinases: a tail of a frog that became a prince

Design and therapeutic application of matrix metalloproteinase inhibitors.

The physiological role of nitric oxide (NO) in the maintenance of vascular tone, in synaptic transmission and in cellular defence is now firmly established. Recent evidence indicates that NO can also affect mitochondrial function. Here, we review findings indicating that NO — through its interaction with components of the electron-transport chain — might function not only as a physiological regulator of cell respiration, but also to augment the generation of reactive oxygen species by mitochondria, and thereby trigger mechanisms of cell survival or death.

Does nitric oxide modulate mitochondrial energy generation and apoptosis

Integrins, matrix metalloproteases (MMPs), and the cytokine TGF-β have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-β exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-β. Because the latent domain of TGF-β1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-β (SLC) to the cell surface where TGF-β activation could be locally controlled. Here, we show that SLC binds to αvβ8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP–dependent release of active TGF-β, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell–matrix interactions.

/pdf/the-integrin-avb8-mediates-epithelial-homeostasis-through-elmhupth3r.pdf

The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1

E‐cadherin controls a wide array of cellular behaviors including cell–cell adhesion, differentiation and tissue development. Here we show that presenilin‐1 (PS1), a protein involved in Alzheimer9s disease, controls a γ‐secretase‐like cleavage of E‐cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E‐cadherin residues Leu731 and Arg732 at the membrane–cytoplasm interface. The PS1/γ‐secretase system cleaves both the full‐length E‐cadherin and a transmembrane C‐terminal fragment, derived from a metalloproteinase cleavage after the E‐cadherin ectodomain residue Pro700. The PS1/γ‐secretase cleavage dissociates E‐cadherins, β‐catenin and α‐catenin from the cytoskeleton, thus promoting disassembly of the E‐cadherin–catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E‐cadherin to the cytosol and increases the levels of soluble β‐ and α‐catenins. Thus, the PS1/γ‐secretase system stimulates disassembly of the E‐cadherin– catenin complex and increases the cytosolic pool of β‐catenin, a key regulator of the Wnt signaling pathway.

/pdf/a-presenilin-1-g-secretase-cleavage-releases-the-e-cadherin-1du1dt8tl8.pdf

A presenilin‐1/γ‐secretase cleavage releases the E‐cadherin intracellular domain and regulates disassembly of adherens junctions

RICHARD E. GALARDYP MARIE E. CASSABONNE, C A R L A ” E GIESE, JAMES H. GILBERT, FRANCE LAPIERRE, HENRY LOPEZ, MARY E. SCHAEFER, ROBERT STACK, MICHAEL SULLIVAN, BRENT SUMMERS, ROB TRESSLER, DAVE TYRRELL, AND JENNIFER WEEC; SCOTT D. ALLEN AND JOHN J. CASTELLO@; JOHN P. BARLETTA AND GREGORY S. SCHULTZe; LEONARD0 A. FERNANDEZf; SUSAN FISHER AND TIAN-YI CUF; HARALD G. FOELLMERh; DAMIAN GROBELNY’; AND WALTER M. HOLLERANJ

Rob Tressler

Papers

Low Molecular Weight Inhibitors in Corneal Ulcerationa