Plateletderived Growth Factor Pdgf

with mannose phosphate. Dimerization follows to a 110-kDa inactive precursor. The precursor has to be activated in a process that is not well understood, but one that may involve proteases. TGF-/3 in serum is bound to a2-macroglobulin, which is cleared by the liver; however, the latent complex of TGF-/3 has an extended half-life and is probably activated by proteases and binding to the IGF-II receptor through substituent mannose 6-phosphate residues. This complex between latent TGF-/3 and IGF-II receptor may be the best conformational form to allow the activating proteases to attack the latent TGF-/3. Latency is apparently a function of the content of sialyl substituents. Binding of latent TGF-/3 to IGF-II receptor could also facilitate endocytosis of the complex to avail the latent TGF-/3 to the lysosomes and an activating environment. The active TGF-/3 is a 12.5-kDa peptide in the form of a 25-kDa homodimer linked by disulfide bonds.

There is a membrane-binding protein that forms a 300-kDa complex with TGF-/3. The function of the binding protein is unknown except that it contains large amounts of heparin sulfate and chondroitin sulfate. This complex may represent a storage form of TGF-/3. The signal-transducing form of TGF-/3 appears

PDGF consists of two chains, A and B, which are separate gene products joined by a disulfide bond. Consequently, three forms of PDGF exist: PDGF-AA, PDGF-AB, and PDGF-BB. The molecular weight of the dimer is about 30 kDa, the A chain being 12 kDa and the B chain 18 kDa. Human platelets contain all three isoforms. PDGF-AA has been found in the context of the osteosarcoma cell-derived growth factor (ODGF), and PDGF-BB has been found in the context of p28sis secreted by simian sarcoma virus-infected cells. PDGF-AA is a secreted form of the growth factor, whereas PDGF-BB is associated with intracellular compartments.

There are two PDGF receptors, a and f3. Both receptors have five extracellular Ig-like domains and intracellular tyrosine kinase domains (Figure 19-10). When the dimeric ligand binds to a receptor, a receptor dimer is formed that is capable of activating the signal transduction process, including autophosphorylation of intracellular tyrosine residues as an initial step. It is of interest that both receptors a and (i induce signal transduction, but only the /3-receptor is involved in chemo-taxis. The a-receptor binds both the A and B chains of PDGF, but the /3-receptor binds only the B chain of the growth factor. Thus, receptor dimer aa binds PDGF-

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