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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Yokote K, Margolis B, Heldin CH, Claesson-Welsh L.; ''Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors.''; PubMedEurope PMCScholia
Yokote K, Hellman U, Ekman S, Saito Y, Rönnstrand L, Saito Y, Heldin CH, Mori S.; ''Identification of Tyr-762 in the platelet-derived growth factor alpha-receptor as the binding site for Crk proteins.''; PubMedEurope PMCScholia
Kashishian A, Kazlauskas A, Cooper JA.; ''Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo.''; PubMedEurope PMCScholia
Kashishian A, Cooper JA.; ''Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase C gamma 1.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Rönnstrand L, Mori S, Arridsson AK, Eriksson A, Wernstedt C, Hellman U, Claesson-Welsh L, Heldin CH.; ''Identification of two C-terminal autophosphorylation sites in the PDGF beta-receptor: involvement in the interaction with phospholipase C-gamma.''; PubMedEurope PMCScholia
Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP, Rao M, Creighton CJ, Hilsenbeck SG, Shaw CA, Muzny D, Gibbs RA, Wheeler DA, Osborne CK, Schiff R, Bentires-Alj M, Elledge SJ, Westbrook TF.; ''Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Somasundaram R, Schuppan D.; ''Type I, II, III, IV, V, and VI collagens serve as extracellular ligands for the isoforms of platelet-derived growth factor (AA, BB, and AB).''; PubMedEurope PMCScholia
Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, Walsh CT, Neel BG.; ''Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor.''; PubMedEurope PMCScholia
Nishimura R, Li W, Kashishian A, Mondino A, Zhou M, Cooper J, Schlessinger J.; ''Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.''; PubMedEurope PMCScholia
Satoh T, Fantl WJ, Escobedo JA, Williams LT, Kaziro Y.; ''Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types.''; PubMedEurope PMCScholia
Heldin CH, Westermark B.; ''Mechanism of action and in vivo role of platelet-derived growth factor.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
Fredriksson L, Li H, Eriksson U.; ''The PDGF family: four gene products form five dimeric isoforms.''; PubMedEurope PMCScholia
Gelderloos JA, Rosenkranz S, Bazenet C, Kazlauskas A.; ''A role for Src in signal relay by the platelet-derived growth factor alpha receptor.''; PubMedEurope PMCScholia
Kazlauskas A, Kashishian A, Cooper JA, Valius M.; ''GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit.''; PubMedEurope PMCScholia
Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Fantl WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT.; ''Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Raines EW, Lane TF, Iruela-Arispe ML, Ross R, Sage EH.; ''The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors.''; PubMedEurope PMCScholia
Heldin CH, Ostman A, Rönnstrand L.; ''Signal transduction via platelet-derived growth factor receptors.''; PubMedEurope PMCScholia
Ostman A, Thyberg J, Westermark B, Heldin CH.; ''PDGF-AA and PDGF-BB biosynthesis: proprotein processing in the Golgi complex and lysosomal degradation of PDGF-BB retained intracellularly.''; PubMedEurope PMCScholia
Stover DR, Furet P, Lydon NB.; ''Modulation of the SH2 binding specificity and kinase activity of Src by tyrosine phosphorylation within its SH2 domain.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
Meisenhelder J, Suh PG, Rhee SG, Hunter T.; ''Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro.''; PubMedEurope PMCScholia
Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M.; ''Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Mori S, Rönnstrand L, Yokote K, Engström A, Courtneidge SA, Claesson-Welsh L, Heldin CH.; ''Identification of two juxtamembrane autophosphorylation sites in the PDGF beta-receptor; involvement in the interaction with Src family tyrosine kinases.''; PubMedEurope PMCScholia
Arvidsson AK, Rupp E, Nånberg E, Downward J, Rönnstrand L, Wennström S, Schlessinger J, Heldin CH, Claesson-Welsh L.; ''Tyr-716 in the platelet-derived growth factor beta-receptor kinase insert is involved in GRB2 binding and Ras activation.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Valgeirsdóttir S, Paukku K, Silvennoinen O, Heldin CH, Claesson-Welsh L.; ''Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Coughlin SR, Escobedo JA, Williams LT.; ''Role of phosphatidylinositol kinase in PDGF receptor signal transduction.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
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 RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
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.
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.
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.
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. PDGF-A chains are expressed as two different isoforms, a longer and a shorter form.The longer (241 aa) is less common and differs from the shorter one (196 aa) by a C-terminal extension of 18 aa (Beckmann et al. 1988, Ostman et al. 1992). The PDGF-A chains are cleaved singly at the RRKR sequence at 86 position to yield predominantly, the secreted PDGF-AA forms, while PDGF-BB are reported that at least three forms of PDGF-BB can be formed (Seidah & Prat 2002). This includes an approx 24 kDa form retained intracellularly and degraded in lysosomes, a secreted approx 30 kDa form and an approx 40 kDa cell surface-associated form. PDGF-B is processed at the 'RGRR' sequence at position 81 and a second clevage close to residues 'ARPVT' at position 190 (Siegfried et al. 2005, Ostman et al. 1992, Heldin & Westermark 1999).
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
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.
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 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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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 have 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.
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.
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
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
Protein tyrosine phosphatase PTNP12 dephosphorylates activated PDFRB (PDGF receptor beta) at tyrosine residue Y1021, which contributes to the tumor suppressor role of PTPN12 in triple negative breast cancer in addition to PTPN12-mediated dephosphorylation of ERBB2 (HER2) at Y1248 (Sun et al. 2011).
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. PDGF-A chains are expressed as two different isoforms, a longer and a shorter form.The longer (241 aa) is less common and differs from the shorter one (196 aa) by a C-terminal extension of 18 aa (Beckmann et al. 1988, Ostman et al. 1992). The PDGF-A chains are cleaved singly at the RRKR sequence at 86 position to yield predominantly, the secreted PDGF-AA forms, while PDGF-BB are reported that at least three forms of PDGF-BB can be formed (Seidah & Prat 2002). This includes an approx 24 kDa form retained intracellularly and degraded in lysosomes, a secreted approx 30 kDa form and an approx 40 kDa cell surface-associated form. PDGF-B is processed at the 'RGRR' sequence at position 81 and a second clevage close to residues 'ARPVT' at position 190 (Siegfried et al. 2005, Ostman et al. 1992, Heldin & Westermark 1999).
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. PDGF-A chains are expressed as two different isoforms, a longer and a shorter form.The longer (241 aa) is less common and differs from the shorter one (196 aa) by a C-terminal extension of 18 aa (Beckmann et al. 1988, Ostman et al. 1992). The PDGF-A chains are cleaved singly at the RRKR sequence at 86 position to yield predominantly, the secreted PDGF-AA forms, while PDGF-BB are reported that at least three forms of PDGF-BB can be formed (Seidah & Prat 2002). This includes an approx 24 kDa form retained intracellularly and degraded in lysosomes, a secreted approx 30 kDa form and an approx 40 kDa cell surface-associated form. PDGF-B is processed at the 'RGRR' sequence at position 81 and a second clevage close to residues 'ARPVT' at position 190 (Siegfried et al. 2005, Ostman et al. 1992, Heldin & Westermark 1999).
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with retention
motifreceptor:PDGF chain
B homodimerdimers (AA, BB,
A/B, CC, DD)dimers (AA, BB,
A/B, CC, DD)receptor
dimer:Crk:p130Cas:C3Greceptor
dimer:Grb2:Sos1receptor
dimer:MyrG-SRCreceptor
dimer:MyrG-p-Y419-SRCreceptor
dimer:PLC-gammaalpha-beta dimer:PDGF AB or BB
dimersreceptor:PDGF
dimersreceptor: PDGF
chain B homodimerreceptor
homodimer:GAPThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
heterodimers dephosphorylated at
Y1021endopeptidases involved in novel
PDGF processingAnnotated Interactions
with retention
motifreceptor:PDGF chain
B homodimerreceptor:PDGF chain
B homodimerdimers (AA, BB,
A/B, CC, DD)dimers (AA, BB,
A/B, CC, DD)receptor
dimer:Crk:p130Cas:C3Greceptor
dimer:Grb2:Sos1receptor
dimer:Grb2:Sos1receptor
dimer:MyrG-SRCreceptor
dimer:MyrG-SRCreceptor
dimer:MyrG-SRCreceptor
dimer:MyrG-p-Y419-SRCreceptor
dimer:PLC-gammareceptor
dimer:PLC-gammareceptor
dimer:PLC-gammaalpha-beta dimer:PDGF AB or BB
dimersreceptor:PDGF
dimersreceptor: PDGF
chain B homodimerreceptor: PDGF
chain B homodimerreceptor
homodimer:GAPThe 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 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 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
heterodimers dephosphorylated at
Y1021endopeptidases involved in novel
PDGF processing