Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell.
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Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
Once phosphorylated, PLCgamma dissociates from the receptor. The active enzyme promotes intracelllular signaling by catalysing the hydrolysis of PIP2 to generate the second messengers IP3 and DAG.
PI3K's preferred substrate is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] which is phosphorylated to the trisphosphate [PI(3,4,5)P3]. PI3-kinase and its products have been found to be of importance in PDGF-stimulated actin reorganization, and directed cell movement, as well as in the stimulation of cell growth and inhibition of apoptosis.
The long splice version of the PDGF-A chain as well as the COOH-terminal part of the PDGF-B precursor contain C-terminal protein motifs that confer retention of the secreted factors. In both the PDGF A- and B-chains, exon 6 encodes a basic sequence that mediates interaction with components of the extracellular matrix. PDGF binds to various types of collagens, thrombospondin and osteopontin; however, the major component of the matrix involved in PDGF binding is likely to be haparan sulphate. The negatively charged sulfate groups on the disaccharide building blocks of heparan sulfate (HS) polysaccharide chains provide binding sites for positively charged amino acid sequence motifs. The precursor of the B-chain may be retained in the matrix; after maturation when the COOH-terminal retention sequence has been cleaved off, the molecule may become more diffusible.
During the extracellular proteolytic activation of PDGF-C and PDGF-D chains, the CUB domains is removed and plasmin protease has been shown to proteolytically cleave within the hinge regions, and thus releasing the corresponding growth factor domains. In addition the protease tissue-type plasminogen activator (tPA) is also involved in the activation of PDGF-CC but not able to cleave and activate PDGF-DD.
Grb2 is an adaptor molecule containing one SH2 domain and two SH3 domains. The SH2 domain of Grb2 binds directly to autophosphorylated PDGF receptors and with its SH3 domain it forms a complex with Sos1. The binding of Grb2/Sos1 to the PDGF receptor juxtaposes the complex towards Ras molecules leading to Ras activation. Ras is implicated in the MAP kinase cascade, a pathway in cell growth stimulation, migration and differentiation.
SOS is the guanine nucleotide exchange factor (GEF) for Ras. SOS activates Ras nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).
Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex. The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites
Crk family of adaptor molecules consists of CrkI with one SH2 and one SH3 domains and CrkII and CrkL with one SH2 and two SH3 domains each. They bind to Tyr762 of the PDGF alpha-receptor and represent the only known SH2-domain containing molecule which binds with significantly higher affinity to the alpha-receptor than to the beta-receptor.
GTPase-activating protein (GAP) has two SH2 domains which bind only to PDGF beta-receptors on Tyr771. GAP does not bind the alpha-receptor. GAP converts Ras-GTP to Ras-GDP, deactivating Ras.
The presence of both SH2 and SH3 domains in Crk proteins is of crucial importance for their function as adaptor molecules. Crk forms complex with Cas, an SH3 domain-containing docking protein which has been shown to be phosphorylated after PDGF-stimulation of cells, and C3G, a nucleotide exchange protein which has been linked to the activation of JNK.
Protein-tyrosine phosphatase 2C (SHP2) is ubiquitously expressed and has two SH2 domains, both of which need to be bound to phosphorylated tyrosine residues for full activation of catalytic activity. SHP-2 binds with high affinity to Tyr 1009 of the PDGF beta-receptor and with lower affinity to Tyr 763; it also binds to the alpha-receptor and Tyr 720 in the interkinase domain has been implicated in this binding. The phosphatase is able to dephosphorylate autophosphorylated PDGF receptors and substrates for PDGF receptors so SHP2 can be thought of as a negative regulator of signaling from PDGF receptors. SHP2 may be involved in positive signaling by binding Grb2/Sos1 and dephosphorylating the COOH-terminal tyrosine of Src, factors important for Src activation.
Among the seven members of the Stat family, Stat1, Stat3, Stat5 alpha and -beta, and Stat6 have been shown to bind to the activated PDGF beta-receptor and to be phosphorylated after PDGF stimulation; binding also occurs to the alpha-receptor, albeit only weakly.
Activation of Src kinases involves displacement of Tyr527 from the SH2 domain and phosphorylation of other tyrosine residues in the kinase domain. Src activation appears to be important for the mitogenic response of PDGF.
Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex. The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites
Nck is a widely expressed protein consisting exclusively of SH2 and SH3 domains. With its SH2 doamin Nck interacts with Tyr571 of the PDGF beta-receptor and it also interacts with the alpha-receptor, but the sites of interaction has not been determined. Nck is involved in the activation of the JNK serine/threonine kinase through interaction with the serine/threonine kinases PAK1 and NIK.
PLC-gamma 1 has been shown to bind to phosphorylated Tyr 1021 of the PDGF beta-receptor with high affinity and to Tyr 1009 with low affinity. In the alpha-receptor, Tyr 988 and Tyr 1018 bind PLC-gamma1. Association of PLC-gamma1 with the activated PDGF receptor has been shown to be necessary for its activation.
Novel PDGFs both PDGF-CC and PDGF-DD dimers are secreted as latent factors without removal of the N-terminal CUB domain. These require further activation by extracellular proteolysis.
Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex. The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites
The Src family of tyrosine kinases are characterized by a SH3 and a SH2 domain in addition to the kinase domain.Src is activated when the SH2 domain binds to autophosphorylation sites on PDGF receptors (Tyr579 and 581 in the beta-receptor, Tyr572 and 574 in the alpha receptor), in conjuction with dephosporylation of the COOH-terminal phosphorylated tyrosine 527.
All the newly synthesized PDGF chains are dimerized in the ER and thereafter transferred to the Golgi complex for proteolytic processing. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD.
Phosphatidylinositol 3'-kinases (PI3Ks) are a family of enzymes which can phosphorylate phosphoinositides. These bind to and are activated by PDGF receptors. Tyr 740 and tyr 751 in PDGF beta-receptor, and tyr 731 and tyr 742 in PDGF alpha-receptor have been shown to be autophosphorylation sites and to bind PI3-kinase.
After dimerization of the PDGF-A and PDGF-B chains in the ER of producing cells, the dimers are proteolytically cleaved in the trans-Golgi network during protein maturation and secretion. The dibasic-specific proprotein convertase, furin, or related convertases are involved in the conversion of proPDGF forms to active PDGF forms.
Grb7 an adapter protein contains a single SH2 domain, a pleckstrin homology (PH) domain, and a proline-rich region. Similar to Grb2, Grb7 interacts with phosphorylated tyrosines in pYXNX motifs, including Tyr716 and Tyr775 of the PDGF beta-receptor.
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DataNodes
Phospho-PDGF receptor dimer Crk p130Cas
C3GPhospho-PDGF receptor dimer
CrkPhospho-PDGF receptor dimer Grb2
Sos1Phospho-PDGF receptor dimer
Grb7Phospho-PDGF receptor dimer
PI3KPhospho-PDGF receptor dimer
PLC-gammaPhospho-PDGF receptor dimer
SHP2Phospho-PDGF receptor dimer
SrcPhospho-PDGF receptor dimer
phospho-SrcPhospho-PDGFR receptor dimer
Nckp-PDGFR dimer
p-PLCgammaphospho-PDGF receptor dimer
STATAnnotated Interactions
Phospho-PDGF receptor dimer
CrkPhospho-PDGF receptor dimer Grb2
Sos1Phospho-PDGF receptor dimer
PI3KPhospho-PDGF receptor dimer
PLC-gammaPhospho-PDGF receptor dimer
SrcPhospho-PDGF receptor dimer
phospho-SrcThe precursor of the B-chain may be retained in the matrix; after maturation when the COOH-terminal retention sequence has been cleaved off, the molecule may become more diffusible.
The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites
The phosphatase is able to dephosphorylate autophosphorylated PDGF receptors and substrates for PDGF receptors so SHP2 can be thought of as a negative regulator of signaling from PDGF receptors. SHP2 may be involved in positive signaling by binding Grb2/Sos1 and dephosphorylating the COOH-terminal tyrosine of Src, factors important for Src activation.
The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites
The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites