A major role of growth factors is to stimulate the activity of genes that are required for cell growth and cell division. Growth factor activity is mediated through binding to specific receptors, ultimately influencing the expression of genes that can:

• Promote entry of cells into the cell cycle

• Relieve blocks on cell cycle progression (thus promoting replication)

• Prevent apoptosis

• Enhance biosynthesis of cellular components (nucleic acids, proteins, lipids, carbohydrates) required for a mother cell to give rise to two daughter cells

Although growth factors are characteristically thought of as proteins that stimulate cell proliferation and/or survival, it is important to remember that they can also drive a host of nongrowth activities, including migration, differentiation, and synthetic capacity.

Growth factors are involved in the proliferation of cells at steady state as well as after injury, when irreversibly damaged cells must be replaced. Uncontrolled proliferation can result when the growth factor activity is dysregulated, or when growth factor signaling pathways are altered to become constitutively active. Thus, many growth factor pathway genes are proto-oncogenes; gain-of-function mutations in these genes can convert them into oncogenes capable of driving unfettered cell proliferation and tumor formation. Table 1 (and the following discussion) summarizes selected growth factors that are involved in two important proliferative processes, tissue repair and tumor development. Although the growth factors described here all involve receptors with intrinsic kinase activity, other growth factors may signal through each of the various pathways shown in Figure 1.

Table1. Growth Factors Involved in Regeneration and Repair

Fig1. Receptor-mediated signaling. A, Categories of signaling receptors, including receptors that utilize a nonreceptor tyrosine kinase; a receptor tyrosine kinase; a nuclear receptor that binds its ligand and can then influence transcription; a seven-transmembrane receptor linked to heterotrimeric G proteins; Notch, which recognizes a ligand on a distinct cell and is cleaved yielding an intracellular fragment that can enter the nucleus and influence transcription of specific target genes; and the Wnt/Frizzled pathway where activation releases intracellular β-catenin from a protein complex that normally drives its constitutive degradation. The released β-catenin can then migrate to the nucleus and act as a transcription factor. Lrp5/Lrp6, low-density-lipoprotein (LDL) receptor related proteins 5 and 6, are highly homologous and act as co-receptors in Wnt/Frizzled signaling. B, Signaling from a tyrosine kinase-based receptor. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins couples the receptor to inactive, GDP-bound RAS, allowing the GDP to be displaced in favor of GTP and yielding activated RAS. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates MAPK (mitogen-activated protein kinase) and activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating cellular responses. The phosphorylated tyrosine kinase receptor can also bind other components, such as phosphatidyl 3-kinase (PI3 kinase), which activates other signaling systems. The cascade is turned off when the activated RAS eventually hydrolyzes GTP to GDP converting RAS to its inactive form. Mutations in RAS that lead to delayed GTP hydrolysis can thus lead to augmented proliferative signaling. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; mTOR, mammalian target of rapamycin.

Epidermal Growth Factor and Transforming Growth Factor-α. Both of these factors belong to the EGF family and bind to the same receptors, which explains why they share many biologic activities. EGF and TGF-α are produced by macrophages and a variety of epithelial cells, and are mitogenic for hepatocytes, fibroblasts, and a host of epithelial cells. The “EGF receptor family” includes four membrane receptors with intrinsic tyrosine kinase activity; the best-characterized is EGFR1, also known as ERB-B1, or simply EGFR. EGFR1 mutations and/or amplification frequently moccur in a number of cancers including those of the lung, head and neck, breast, and brain. The ERBB2 receptor (also known as HER2) is overexpressed in a subset of breast cancers. Many of these receptors have been successfully targeted by antibodies and small molecule antagonists.

Hepatocyte Growth Factor. Hepatocyte growth factor (HGF; also known as scatter factor) has mitogenic effects on hepatocytes and most epithelial cells, including biliary, pulmonary, renal, mammary,and epidermal. HGF acts as a morphogen in embryonic development (i.e., it influences the pattern of tissue differentiation), promotes cell migration (hence its designation as scatter factor), and enhances hepatocyte survival. HGF is produced by fibroblasts and most mesenchymal cells, as well as endothelium and nonhepatocyte liver cells. It is synthesized as an inactive precursor (pro-HGF) that is proteolytically activated by serine proteases released at sites of injury. MET is the receptor for HGF, it has intrinsic tyrosine kinase activity and is frequently overexpressed or mutated in tumors, particularly renal and thyroid papillary carcinomas. Consequently, MET inhibitors may be of value for cancer therapy.

Platelet-Derived Growth Factor. Platelet-derived growth factor (PDGF) is a family of several closely related proteins, each consisting of two chains (designated by pairs of letters). Three isoforms of PDGF (AA, AB, and BB) are constitutively active; PDGF-CC and PDGF-DD must be activated by proteolytic cleavage. PDGF is stored in platelet granules and is released on platelet activation. Although originally isolated from platelets (hence the name), it is also produced by many other cells, including activated macrophages, endothelium, smooth muscle cells, and a variety of tumors. All PDGF isoforms exert their effects by binding to two cell surface receptors (PDGFR α and β), both having intrinsic tyrosine kinase activity. PDGF induces fibroblast, endothelial, and smooth muscle cell proliferation and matrix synthesis, and is chemotactic for these cells (and inflammatory cells), thus promoting recruitment of the cells into areas of inflammation and tissue injury.

Vascular Endothelial Growth Factor. Vascular endothelial growth factors (VEGFs)—VEGF-A, -B, -C, and -D, and PIGF (placental growth factor)—are a family of homodimeric proteins. VEGF-A is generally referred to simply as VEGF; it is the major angiogenic factor (inducing blood vessel development) after injury and in tumors. In comparison, VEGF-B and PlGF are involved in embryonic vessel development, and VEGF-C and -D stimulate both angiogenesis and lymphatic development (lymphangiogenesis). VEGFs are also involved in the maintenance of normal adult endothelium (i.e., not involved in angiogenesis), with the highest expression in epithelial cells adjacent to fenestrated epithelium (e.g., podocytes in the kidney, pigment epithelium in the retina, and choroid plexus in the brain). VEGF induces angiogenesis by promoting endothelial cell migration, proliferation (capillary sprouting), and formation of the vascular lumen. VEGFs also induce vascular dilation and increased vascular permeability. As might be anticipated, hypoxia is the most important inducer of VEGF production, through pathways that involve intracellular hypoxia-inducible factor (HIF-1). Other VEGF inducers—produced at sites of inflammation or wound healing—include PDGF and TGF-α.

VEGFs bind to a family of receptor tyrosine kinases (VEGFR-1, -2, and -3); VEGFR-2 is highly expressed in endothelium and is the most important for angiogenesis. Antibodies against VEGF are approved for the treatment of several tumors such as renal and colon cancers since they require angiogenesis for their spread and growth. Anti-VEGF antibodies are also being used for a number of ophthalmic diseases including “wet” age-related macular degeneration (AMD is a disorder of inappropriate angiogenesis and vascular permeability that causes adult-onset blindness); the angiogenesis associated with retinopathy of prematurity; and the leaky vessels that lead to diabetic macular edema. Finally, increased levels of soluble versions of VEGFR-1 (s-FLT-1) in pregnant women may cause preeclampsia (hypertension and proteinuria) by “sopping up” the free VEGF required for maintaining normal endothelium.

Fibroblast Growth Factor. Fibroblast growth factor (FGF) is a family of growth factors with of 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 extracellular matrix, 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, which is distinct from TGF-α, has three isoforms (TGF-β1, TGF-β2, TGF-β3), each belonging to a family of about 30 members that includes bone morphogenetic proteins (BMPs), activins, inhibins, and müllerian inhibiting substance. TGF-β1 has the most widespread distribution, and is more commonly referred to as 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 (types I and II), both with serine/threonine kinase activity that induce the phosphorylation of a variety of 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 has multiple and often opposing effects depending on the tissue and concurrent signals. Agents with such multiplicity of effects are called pleiotropic. Because of the bewildering diversity of TGF-β effects (see later), this growth factor is said to be “pleiotropic with a vengeance.” Primarily, however, TGF-β drives scar formation, and applies brakes on the inflammation that accompanies wound healing.

• TGF-β stimulates the production of collagen, fibronectin, and proteoglycans, and it inhibits collagen degradation by both decreasing matrix metalloproteinase (MMP) activity and increasing the activity of tissue inhibitors of proteinases (TIMPs; discussed later). TGF-β is involved not only in scar formation after injury, but also drives fibrosis in lung, liver, and kidneys in the setting of chronic inflammation.

• TGF-β is an antiinflammatory cytokine that serves to limit and terminate inflammatory responses. It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes. Animal models lacking TGF-β have widespread and persistent inflammation.

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مواضيع ذات صلة

Stem Cells

Proliferation and the Cell Cycle

Signal Transduction Pathways

Cell Signaling

Cellular Metabolism and Mitochondrial Function

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

Plasma Membrane: Protection and Nutrient Acquisition

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation