Fibroblast growth factor. Fibroblast growth factor (FGF) is a family of growth factors with more than 20 members. Acidic FGF (aFGF, or FGF-1) and basic FGF (bFGF, or FGF-2) are the best characterized; FGF-7 is also referred to as keratinocyte growth factor (KGF). Released FGFs associate with heparan sulfate in the ECM, which serves as a reservoir for inactive factors that can be subsequently released by proteolysis (e.g., at sites of wound healing). FGFs transduce signals through four tyrosine kinase receptors (FGFR 1–4). FGFs contribute to wound healing responses, hematopoiesis, and development; bFGF has all the activities necessary for angiogenesis as well.
Transforming growth factor-β. TGF-β has three isoforms (TGF-β1, TGF-β2, and TGF-β3) that belong to a family with about 30 members, including bone morphogenetic proteins (BMPs), activins, inhibins, and Müllerian inhibiting substance. TGF-β1 has the most widespread distribution, and it is more commonly referred to simply as http://ebooksmedicine.net
TGF-β. It is a homodimeric protein produced by multiple cell types, including platelets, endothelium, and mononuclear inflammatory cells. TGF-β is secreted as a precursor that requires proteolysis to yield the biologically active protein. There are two TGF-β receptors, both with serine/threonine kinase activity that induces the phosphorylation of several downstream cytoplasmic transcription factors called Smads. Phosphorylated Smads form heterodimers with Smad4, allowing nuclear translocation and association with other DNA-binding proteins to activate or inhibit gene transcription. TGF-β produces multiple and often opposing effects depending on the tissue type and concurrent signals. Agents with such multiplicity of effects are called pleiotropic, and TGF-β is “pleiotropic with a vengeance.” Primarily, TGF-β drives scar formation by stimulating matrix synthesis through decreased matrix metalloproteinase (MMP) activity and increased activity of tissue inhibitors of proteinases (TIMPs). TGF-β also applies brakes to the inflammation that accompanies wound healing by inhibiting lymphocyte proliferation and the activity of other leukocytes.
The ECM is a network of interstitial proteins that constitutes a significant proportion of any tissue. Cell interactions with ECM are critical for development and healing, as well as for maintaining normal tissue architecture (
Fig.
1.13 ). Much more than a simple “space filler” around cells, ECM serves several key functions:
Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity.
Control of cell proliferation, by binding and displaying growth factors and by signaling through cellular receptors of the integrin family. The ECM provides a depot
PROLIFERATION, DIFFERENTIATION, PROTEIN SYNTHESIS, ATTACHMENT, MIGRATION, SHAPE CHANGE
Fig. 1.13 Interactions of ECM and growth factor–mediated cell signaling. Cell surface integrins interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, α-actinin, and talin; see