Signaling by PDGF (Homo sapiens)

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Bibliography

1. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
2. Yokote K, Margolis B, Heldin CH, Claesson-Welsh L.; ''Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors.''; PubMed Europe PMC Scholia
3. 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.''; PubMed Europe PMC Scholia
4. Kashishian A, Kazlauskas A, Cooper JA.; ''Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo.''; PubMed Europe PMC Scholia
5. Kashishian A, Cooper JA.; ''Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase C gamma 1.''; PubMed Europe PMC Scholia
6. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
7. 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.''; PubMed Europe PMC Scholia
8. 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.''; PubMed Europe PMC Scholia
9. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
10. 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).''; PubMed Europe PMC Scholia
11. 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.''; PubMed Europe PMC Scholia
12. 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.''; PubMed Europe PMC Scholia
13. 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.''; PubMed Europe PMC Scholia
14. Heldin CH, Westermark B.; ''Mechanism of action and in vivo role of platelet-derived growth factor.''; PubMed Europe PMC Scholia
15. 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.''; PubMed Europe PMC Scholia
16. Hogg PJ, Hotchkiss KA, Jiménez BM, Stathakis P, Chesterman CN.; ''Interaction of platelet-derived growth factor with thrombospondin 1.''; PubMed Europe PMC Scholia
17. Fredriksson L, Li H, Eriksson U.; ''The PDGF family: four gene products form five dimeric isoforms.''; PubMed Europe PMC Scholia
18. Gelderloos JA, Rosenkranz S, Bazenet C, Kazlauskas A.; ''A role for Src in signal relay by the platelet-derived growth factor alpha receptor.''; PubMed Europe PMC Scholia
19. 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.''; PubMed Europe PMC Scholia
20. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed Europe PMC Scholia
21. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
22. 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.''; PubMed Europe PMC Scholia
23. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
24. 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.''; PubMed Europe PMC Scholia
25. Heldin CH, Ostman A, Rönnstrand L.; ''Signal transduction via platelet-derived growth factor receptors.''; PubMed Europe PMC Scholia
26. 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.''; PubMed Europe PMC Scholia
27. Stover DR, Furet P, Lydon NB.; ''Modulation of the SH2 binding specificity and kinase activity of Src by tyrosine phosphorylation within its SH2 domain.''; PubMed Europe PMC Scholia
28. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
29. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
30. 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.''; PubMed Europe PMC Scholia
31. Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M.; ''Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins.''; PubMed Europe PMC Scholia
32. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC Scholia
33. 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.''; PubMed Europe PMC Scholia
34. 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.''; PubMed Europe PMC Scholia
35. 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.''; PubMed Europe PMC Scholia
36. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
37. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
38. 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.''; PubMed Europe PMC Scholia
39. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
40. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
41. Coughlin SR, Escobedo JA, Williams LT.; ''Role of phosphatidylinositol kinase in PDGF receptor signal transduction.''; PubMed Europe PMC Scholia
42. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
43. Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMed Europe PMC Scholia
44. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
45. 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.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
3x4Hyp-3Hyp-5Hyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-5Hyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
5Hyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
5Hyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Active PDGF dimers (AA, AB, BB)		R-HSA-380760 (Reactome)
Active PDGF dimers (CC, DD)		R-HSA-381939 (Reactome)
COL4A1(173-1669)	Protein	P02462 (Uniprot-TrEMBL)
COL4A2(184-1712)	Protein	P08572 (Uniprot-TrEMBL)
COL4A3(29-1670)	Protein	Q01955 (Uniprot-TrEMBL)
COL4A4(39-?)	Protein	P53420 (Uniprot-TrEMBL)
COL4A5(27-?)	Protein	P29400 (Uniprot-TrEMBL)
COL6A1	Protein	P12109 (Uniprot-TrEMBL)
COL6A2	Protein	P12110 (Uniprot-TrEMBL)
COL9A1	Protein	P20849 (Uniprot-TrEMBL)
COL9A2	Protein	Q14055 (Uniprot-TrEMBL)
COL9A3	Protein	Q14050 (Uniprot-TrEMBL)
CRK	Protein	P46108 (Uniprot-TrEMBL)
CRK, CRKL		R-HSA-381945 (Reactome)
CRKL	Protein	P46109 (Uniprot-TrEMBL)
Classical PDGF precursor dimers (AA, AB, BB)		R-HSA-186822 (Reactome)
Cleaved classical PDGF peptides		R-HSA-389066 (Reactome)
Cleaved novel PDGF fragments		R-HSA-389070 (Reactome)
DAG and IP3 signaling	Pathway	R-HSA-1489509 (Reactome)	This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
Extracellular matrix ligands		R-HSA-381946 (Reactome)
FURIN	Protein	P09958 (Uniprot-TrEMBL)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GRB2-1	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1	Complex	R-HSA-109797 (Reactome)
GRB7	Protein	Q14451 (Uniprot-TrEMBL)
GRB7	Protein	Q14451 (Uniprot-TrEMBL)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
GalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
GlcGalHyl-COL6A1	Protein	P12109 (Uniprot-TrEMBL)
GlcGalHyl-COL6A2	Protein	P12110 (Uniprot-TrEMBL)
HRAS	Protein	P01112 (Uniprot-TrEMBL)
Heparan sulfate N-acetyl-alpha-D-glucosaminide	Metabolite	CHEBI:17421 (ChEBI)
Heparan sulfate alpha-D-glucosaminide	Metabolite	CHEBI:18137 (ChEBI)
KRAS	Protein	P01116 (Uniprot-TrEMBL)
NCK1	Protein	P16333 (Uniprot-TrEMBL)
NCK1,NCK2		R-HSA-381949 (Reactome)
NCK2	Protein	O43639 (Uniprot-TrEMBL)
NRAS	Protein	P01111 (Uniprot-TrEMBL)
Novel PDGF precursor dimers (CC, DD)		R-HSA-381942 (Reactome)
Novel PDGF precursor dimers (CC, DD)		R-HSA-381947 (Reactome)
P130CAS	Protein	P56945 (Uniprot-TrEMBL)
P130CAS	Protein	P56945 (Uniprot-TrEMBL)
PDGF A and B chains:ECM complex	Complex	R-HSA-381952 (Reactome)
PDGF A and B chains with retention motif		R-HSA-381934 (Reactome)
PDGF alpha receptor: PDGF dimers	Complex	R-HSA-389079 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimers	Complex	R-HSA-389077 (Reactome)
PDGF beta receptor:PDGF chain B homodimer	Complex	R-HSA-389078 (Reactome)
PDGF precursor dimers (AA, BB, A/B, CC, DD)		R-HSA-381936 (Reactome)
PDGF precursor dimers (AA, BB, A/B, CC, DD)		R-HSA-381926 (Reactome)
PDGF receptor monomer		R-HSA-186792 (Reactome)
PDGF:PDGF receptor dimer	Complex	R-HSA-186766 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Crk:p130Cas:C3G	Complex	R-HSA-381957 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Grb2:Sos1	Complex	R-HSA-186827 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PLC-gamma	Complex	R-HSA-186795 (Reactome)
PDGF:Phospho-PDGF receptor dimer:phospho-Src	Complex	R-HSA-380768 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Crk	Complex	R-HSA-381955 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Grb7	Complex	R-HSA-381956 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PI3K	Complex	R-HSA-186789 (Reactome)
PDGF:Phospho-PDGF receptor dimer:SHP2	Complex	R-HSA-186839 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Src	Complex	R-HSA-186831 (Reactome)
PDGF:Phospho-PDGF receptor dimer	Complex	R-HSA-186811 (Reactome)
PDGF:Phospho-PDGFR receptor dimer:Nck	Complex	R-HSA-381954 (Reactome)
PDGF:p-PDGFR dimer:p-PLCgamma	Complex	R-HSA-1524184 (Reactome)
PDGF:phospho-PDGF receptor dimer:STAT	Complex	R-HSA-380766 (Reactome)
PDGFA-1	Protein	P04085-1 (Uniprot-TrEMBL)
PDGFA-2	Protein	P04085-2 (Uniprot-TrEMBL)
PDGFB	Protein	P01127 (Uniprot-TrEMBL)
PDGFB(82-241)	Protein	P01127 (Uniprot-TrEMBL)
PDGFRA	Protein	P16234 (Uniprot-TrEMBL)
PDGFRB	Protein	P09619 (Uniprot-TrEMBL)
PI(3,4,5)P3	Metabolite	CHEBI:16618 (ChEBI)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PI3K	Complex	R-HSA-74693 (Reactome)
PIK3CA	Protein	P42336 (Uniprot-TrEMBL)
PIK3CB	Protein	P42338 (Uniprot-TrEMBL)
PIK3R1	Protein	P27986 (Uniprot-TrEMBL)
PIK3R2	Protein	O00459 (Uniprot-TrEMBL)
PIP3 activates AKT signaling	Pathway	R-HSA-1257604 (Reactome)	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.
PLCG1	Protein	P19174 (Uniprot-TrEMBL)
PLCG1	Protein	P19174 (Uniprot-TrEMBL)
PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
Phospho PDGF alpha-beta dimer:PDGF AB or BB dimers	Complex	R-HSA-389076 (Reactome)
Phospho PDGF alpha receptor:PDGF dimers	Complex	R-HSA-389073 (Reactome)
Phospho PDGF beta receptor: PDGF chain B homodimer	Complex	R-HSA-389074 (Reactome)
Phospho-beta receptor homodimer:GAP	Complex	R-HSA-186830 (Reactome)
RAF/MAP kinase cascade	Pathway	R-HSA-5673001 (Reactome)	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).
RAPGEF1	Protein	Q13905 (Uniprot-TrEMBL)
RAPGEF1	Protein	Q13905 (Uniprot-TrEMBL)
RASA1	Protein	P20936 (Uniprot-TrEMBL)
RASA1	Protein	P20936 (Uniprot-TrEMBL)
SOS1	Protein	Q07889 (Uniprot-TrEMBL)
SPP1	Protein	P10451 (Uniprot-TrEMBL)
SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
STAT family members		R-HSA-380756 (Reactome)
STAT1	Protein	P42224 (Uniprot-TrEMBL)
STAT3	Protein	P40763 (Uniprot-TrEMBL)
STAT5A	Protein	P42229 (Uniprot-TrEMBL)
STAT5B	Protein	P51692 (Uniprot-TrEMBL)
STAT6	Protein	P42226 (Uniprot-TrEMBL)
THBS1	Protein	P07996 (Uniprot-TrEMBL)
THBS2	Protein	P35442 (Uniprot-TrEMBL)
THBS3	Protein	P49746 (Uniprot-TrEMBL)
THBS4	Protein	P35443 (Uniprot-TrEMBL)
p-11Y-PDGFRA	Protein	P16234 (Uniprot-TrEMBL)
p-12Y-PDGFRB	Protein	P09619 (Uniprot-TrEMBL)
p-4Y-PLCG1	Protein	P19174 (Uniprot-TrEMBL)
p-4Y-PLCG1	Protein	P19174 (Uniprot-TrEMBL)
p-Y419-SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
p21 RAS:GDP	Complex	R-HSA-109796 (Reactome)
p21 RAS:GTP	Complex	R-HSA-109783 (Reactome)
serine-type endopeptidases involved in novel PDGF processing		R-HSA-381937 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-186786 (Reactome)
	ADP	Arrow	R-HSA-186800 (Reactome)
	ADP	Arrow	R-HSA-380780 (Reactome)
	ADP	Arrow	R-HSA-389083 (Reactome)
	ADP	Arrow	R-HSA-389086 (Reactome)
ATP			R-HSA-186786 (Reactome)
ATP			R-HSA-186800 (Reactome)
ATP			R-HSA-380780 (Reactome)
ATP			R-HSA-389083 (Reactome)
ATP			R-HSA-389086 (Reactome)
	Active PDGF dimers (AA, AB, BB)	Arrow	R-HSA-186785 (Reactome)
Active PDGF dimers (AA, AB, BB)			R-HSA-186773 (Reactome)
	Active PDGF dimers (CC, DD)	Arrow	R-HSA-382061 (Reactome)
CRK, CRKL			R-HSA-382056 (Reactome)
Classical PDGF precursor dimers (AA, AB, BB)			R-HSA-186785 (Reactome)
	Cleaved classical PDGF peptides	Arrow	R-HSA-186785 (Reactome)
	Cleaved novel PDGF fragments	Arrow	R-HSA-382061 (Reactome)
Extracellular matrix ligands			R-HSA-382054 (Reactome)
FURIN		mim-catalysis	R-HSA-186785 (Reactome)
	GDP	Arrow	R-HSA-186834 (Reactome)
GRB2-1:SOS1			R-HSA-186826 (Reactome)
GRB7			R-HSA-382055 (Reactome)
GTP			R-HSA-186834 (Reactome)
NCK1,NCK2			R-HSA-382058 (Reactome)
	Novel PDGF precursor dimers (CC, DD)	Arrow	R-HSA-382057 (Reactome)
Novel PDGF precursor dimers (CC, DD)			R-HSA-382057 (Reactome)
Novel PDGF precursor dimers (CC, DD)			R-HSA-382061 (Reactome)
P130CAS			R-HSA-382052 (Reactome)
	PDGF A and B chains:ECM complex	Arrow	R-HSA-382054 (Reactome)
PDGF A and B chains with retention motif			R-HSA-382054 (Reactome)
PDGF alpha receptor: PDGF dimers			R-HSA-389083 (Reactome)
PDGF alpha receptor: PDGF dimers		mim-catalysis	R-HSA-389083 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimers			R-HSA-389086 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimers		mim-catalysis	R-HSA-389086 (Reactome)
PDGF beta receptor:PDGF chain B homodimer			R-HSA-186786 (Reactome)
PDGF beta receptor:PDGF chain B homodimer		mim-catalysis	R-HSA-186786 (Reactome)
PDGF precursor dimers (AA, BB, A/B, CC, DD)			R-HSA-382053 (Reactome)
	PDGF precursor dimers (AA, BB, A/B, CC, DD)	Arrow	R-HSA-382053 (Reactome)
PDGF receptor monomer			R-HSA-186773 (Reactome)
	PDGF:PDGF receptor dimer	Arrow	R-HSA-186773 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:Crk:p130Cas:C3G	Arrow	R-HSA-382052 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:Grb2:Sos1	Arrow	R-HSA-186826 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Grb2:Sos1		mim-catalysis	R-HSA-186834 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:PLC-gamma	Arrow	R-HSA-186765 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PLC-gamma			R-HSA-1524186 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PLC-gamma		mim-catalysis	R-HSA-1524186 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:phospho-Src	Arrow	R-HSA-380780 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:Crk	Arrow	R-HSA-382056 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Crk			R-HSA-382052 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:Grb7	Arrow	R-HSA-382055 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:PI3K	Arrow	R-HSA-186780 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PI3K		mim-catalysis	R-HSA-186800 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:SHP2	Arrow	R-HSA-186778 (Reactome)
	PDGF:Phospho-PDGF receptor dimer:Src	Arrow	R-HSA-186819 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Src			R-HSA-380780 (Reactome)
	PDGF:Phospho-PDGF receptor dimer	Arrow	R-HSA-1524182 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-186765 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-186778 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-186780 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-186819 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-186826 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-380782 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-382055 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-382056 (Reactome)
PDGF:Phospho-PDGF receptor dimer			R-HSA-382058 (Reactome)
	PDGF:Phospho-PDGFR receptor dimer:Nck	Arrow	R-HSA-382058 (Reactome)
	PDGF:p-PDGFR dimer:p-PLCgamma	Arrow	R-HSA-1524186 (Reactome)
PDGF:p-PDGFR dimer:p-PLCgamma			R-HSA-1524182 (Reactome)
	PDGF:phospho-PDGF receptor dimer:STAT	Arrow	R-HSA-380782 (Reactome)
	PI(3,4,5)P3	Arrow	R-HSA-186800 (Reactome)
PI(4,5)P2			R-HSA-186800 (Reactome)
PI3K			R-HSA-186780 (Reactome)
PLCG1			R-HSA-186765 (Reactome)
PTPN11			R-HSA-186778 (Reactome)
	Phospho PDGF alpha-beta dimer:PDGF AB or BB dimers	Arrow	R-HSA-389086 (Reactome)
	Phospho PDGF alpha receptor:PDGF dimers	Arrow	R-HSA-389083 (Reactome)
	Phospho PDGF beta receptor: PDGF chain B homodimer	Arrow	R-HSA-186786 (Reactome)
Phospho PDGF beta receptor: PDGF chain B homodimer			R-HSA-186798 (Reactome)
	Phospho-beta receptor homodimer:GAP	Arrow	R-HSA-186798 (Reactome)
			R-HSA-1524182 (Reactome)	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.
			R-HSA-1524186 (Reactome)	The activated PDGF receptor phosphorylates PLCgamma on tyrosine residues 472,771,783 and 1254, activating the enzyme.
			R-HSA-186765 (Reactome)	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.
			R-HSA-186773 (Reactome)	PDGF dimer binds two receptors simultaneously. The receptors dimerise on binding and this is key to receptor autophosphorylation.
			R-HSA-186778 (Reactome)	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.
			R-HSA-186780 (Reactome)	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.
			R-HSA-186785 (Reactome)	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.
			R-HSA-186786 (Reactome)	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
			R-HSA-186798 (Reactome)	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.
			R-HSA-186800 (Reactome)	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.
			R-HSA-186819 (Reactome)	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.
			R-HSA-186826 (Reactome)	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.
			R-HSA-186834 (Reactome)	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).
			R-HSA-380780 (Reactome)	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.
			R-HSA-380782 (Reactome)	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.
			R-HSA-382052 (Reactome)	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.
			R-HSA-382053 (Reactome)	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.
			R-HSA-382054 (Reactome)	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.
			R-HSA-382055 (Reactome)	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.
			R-HSA-382056 (Reactome)	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.
			R-HSA-382057 (Reactome)	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.
			R-HSA-382058 (Reactome)	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.
			R-HSA-382061 (Reactome)	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.
			R-HSA-389083 (Reactome)	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
			R-HSA-389086 (Reactome)	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
RAPGEF1			R-HSA-382052 (Reactome)
RASA1			R-HSA-186798 (Reactome)
SRC-1			R-HSA-186819 (Reactome)
SRC-1		mim-catalysis	R-HSA-380780 (Reactome)
STAT family members			R-HSA-380782 (Reactome)
	p-4Y-PLCG1	Arrow	R-HSA-1524182 (Reactome)
p21 RAS:GDP			R-HSA-186834 (Reactome)
	p21 RAS:GTP	Arrow	R-HSA-186834 (Reactome)
serine-type endopeptidases involved in novel PDGF processing		mim-catalysis	R-HSA-382061 (Reactome)