Platelet Derived Growth Factor

Platelet-derived growth factor (PDGF) family plays important roles in angiogenesis. PDGF is an approximately 30 kilodalton (kDa) protein consisting of four related polypeptide chains (-A, -B, -C, and -D) that exist in dimeric form as a result of disulfide bonds between cysteine residues contained within the peptides. PDGF can form homodimers (-AA, -BB, -CC, and -DD) as well as a heterodimer (-AB). The c-sis/PDGF-2 gene on chromosome 22q that encodes PDGF-B in humans is homologous to the v-sis of the Simian sarcoma virus, which is significant because it is an oncogene.

The PDGF family of proteins binds to and signals through membrane-bound receptor tyrosine kinases (RTKs), of which there are two isoforms: PDGF receptor (PDGFR)-a (170kDa) and -b (190kDa). Similar to their ligands, the PDGFR also form homo- or heterodimers: PDGFR-aa, -ab, and -bb. PDGFR-a and -b arise from two different gene products and have various binding affinities for their PDGF ligands. For example, PDGF-AA binds only the -aa

Blood Vessel

Blood Vessel

Endothelial Cells

Induces Pericyte Recruitment

Blood Vessel

Endothelial Cells

Induces Pericyte Recruitment

Blood Vessel

Endothelial Cells

Fi dP

Pericytes

Figure 1 Schematic Representation of Pericyte Recruitment to a Newly Formed Vessel. PDGF-B released from endothelial and other types of cells acts as a chemoattractant by stimulating PDGFR-ß on vascular support cells called pericytes. This stimulus causes the recruitment of pericytes that encase and structurally stabilize the growing vessel. (see color insert)

receptor homodimer, whereas PDGF-BB interacts with -aa and -ab receptors but has the highest binding affinity for the -bb receptor. The PDGF-AB heterodimer preferentially binds to -aa and -ab receptors. PDGF-CC and PDGF-DD interact with the -aa and -bb receptors, respectively. All of the receptor subtypes are comprised of five immunoglobu-lin-like extracellular domains containing a ligand-binding site, a single hydrophobic transmembrane domain, and an intracellular domain containing residues with tyrosine kinase activity (Figure 2).

Binding of ligand induces receptor homo- or hetero-dimerization depending on cellular expression of the receptor subtype and ligand present. In a process known as autophosphorylation, the kinase portion of each receptor monomer phosphorylates tyrosine residues within the intracellular domain of its dimeric partner. Afterward, additional phosphorylation events occur at other locations within the intracellular domain of the receptor. These phosphorylated tyrosine residues serve as docking sites for signaling molecules that contain SH2 domains such as PI-3 (phos-phatidylinositol-3) kinase, Src (cellular counterpart of the Rous sarcoma virus gene, v-src), Grb2/Sos1 (growth factor receptor-bound protein 2/son of sevenless 1), Stat (signal transducer and activator of transcription), GAP (GTPase activating proteins), and PLC-g (phospholipase Cg), leading to modulation of cellular processes and gene expression. Cellular functions including mitogenesis, chemotaxis, and apoptosis are regulated based on the broad range of signaling cascades to which the PDGF receptors couple.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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