Signaling by PDGF (Homo sapiens)

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25, 26, 344, 2625, 26, 3715, 25, 2611, 25, 2610, 22, 25, 2832614, 267, 26, 43348, 25, 3423, 26, 302620, 26, 392, 4054, 26, 31268, 25, 348, 25, 3418, 24-2640269, 26, 388, 3415, 2634cytosolGolgi lumenplasma membraneplasma membraneendoplasmic reticulum lumenSTAT3 PIP3 activates AKTsignalingp-4Y-PLCG1 ATPPDGFA-2 PDGFA-1 ATPPIK3CB p-11Y-PDGFRA PDGF:Phospho-PDGFreceptor dimer:Grb7PDGFA-1 NCK1 PDGFA-2 Phospho PDGF betareceptor: PDGFchain B homodimerNovel PDGF precursordimers (CC, DD)ADPPDGF:Phospho-PDGFreceptordimer:MyrG-SRCPDGFB(82-241) p-11Y-PDGFRA PDGFB(82-241) PDGFRB p-12Y-PDGFRB PDGFA-1 PDGFA-2 p-12Y-PDGFRB PDGFB(1-241) PDGFA-2 NRAS PDGFB (82-190) SPP1 PDGFB(82-241) PDGFA-2 PTPN11 PTPN11PDGFA-2 PDGF:PDGF receptordimerPDGFA-1 PDGFB (82-190) N-ter PDGFA-2fragmentp-11Y-PDGFRA PLCG1PDGF:Phospho-PDGFreceptordimer:MyrG-p-Y419-SRCCleaved novel PDGFfragmentsp-11Y-PDGFRB PDGFA-2 ADPNCK2 PDGFB (82-190) PDGFB (82-190) HRAS PTPN12PDGFB(82-241) serine-typeendopeptidasesinvolved in novelPDGF processingSTAT1 PDGFRA PLG(20-580) PDGFB(82-241) ADPPDGFA-1 PDGFA-2 STAT5B p-11Y-PDGFRA PDGFB (82-190) PDGFB(82-241) PDGF alpha/beta:PDGFAB and BB dimersp-12Y-PDGFRB PI3KCRK, CRKLPDGFA-1(1-211) RAF/MAP kinasecascadePDGFB(82-241) PDGFC-1 p-11Y-PDGFRA PDGFB (82-190) PDGFA-2 PDGFB(82-241) PDGFB(191-241) PDGFA-2 N-ter PDGFA-1 fragment PDGFRA active PDGF-BB dimerp-12Y-PDGFRB PDGFD(1-370) GRB2-1:SOS1PDGFA-1 p-12Y-PDGFRB PDGFA-2 PDGFA-1 GTP STAT6 PDGFA-2 PDGFB(82-241) PLAT(36-562) RAPGEF1 CRKL p-12Y-PDGFRB SOS1 PIK3CA PDGFA-1 PDGFA-1 STAT family membersPDGFRB PDGFB (82-190) p-12Y-PDGFRB active PDGF-AA dimerPDGF:Phospho-PDGFreceptor dimer:SHP2PDGF:phospho-PDGFreceptor dimer:STATPDGFB (82-190) Phospho PDGF alphareceptor:PDGFdimersGTPGRB2-1 MyrG-p-Y419-SRC p-12Y-PDGFRB GDP Active PDGF dimers(CC, DD)PDGFA-1 PDGF:Phospho-PDGFreceptor dimerPDGFB(1-241) H2OCRKL PDGFRB PIK3R2 PIK3R2 p-12Y-PDGFRB PDGFA-2 PDGFB(82-241) PDGF precursordimers (AA, BB,A/B, CC, DD)Novel PDGF precursordimers (CC, DD)STAT3 PDGFB(82-241) PDGFB(82-241) PDGFB (82-190) GRB7proPDGF-BB dimerPhospho PDGFalpha-betadimer:PDGF AB or BBdimersPDGF precursordimers (AA, BB,A/B, CC, DD)p-11Y-PDGFRA PDGFA-2 p-12Y-PDGFRB PDGFRA PDGFB (82-190) NCK1,NCK2PDGF A and Bchains:ECM complexp-12Y-PDGFRB p-12Y-PDGFRB p-11Y-PDGFRA p21 RAS:GDPMyrG-SRCCRK PDGFD(1-370) PDGFB(82-241) PDGFA-2 Cleaved PDGF-BpeptidesCollagens BCAR1 Thrombospondin PDGFB(82-241) PDGFB (82-190) PDGF:Phospho-PDGFreceptordimer:Grb2:Sos1PDGFB(82-241) p-12Y-PDGFRB PDGFB(82-241) PDGF A and B chainswith retentionmotifPDGFB(82-241) PDGFB (82-190) PDGFA-1 PDGFB (82-190) PDGFA-1 STAT6 PDGFB (82-190) PIK3CB PLG(581-810) PDGFB(82-241) PI(4,5)P2PDGFB (82-190) ATPp-11Y-PDGFRA CRK PDGF betareceptor:PDGF chainB homodimerPDGFC-1 PDGF receptormonomerPDGFA-1 p-12Y-PDGFRB PDGFB(82-241) GRB7 PDGFA-1(1-211) PDGFD(19-370) STAT1 p-11Y-PDGFRA PLCG1 HRAS PIK3CA PDGFD(1-370) FURINPDGFB(1-241) p-11Y-PDGFRA PDGFB (82-190) PDGFA-1(1-211) PDGF:p-PDGFRdimer:p-PLCgammap-11Y-PDGFRA p-11Y-PDGFRA MyrG-SRC PDGFB (82-190) ADPp-12Y-PDGFRB PDGFB(82-241) p-11Y-PDGFRA PDGFA-1 PDGFA-1 PDGFC-1(24-234) proPDGF-AA dimerPhospho-betareceptorhomodimer:GAPPDGFB(82-241) CRKL PDGFA-2 SPP1 PDGFB (82-190) p-11Y-PDGFRA PDGFD(258-370) PDGFB(1-81) RASA1PDGFB(82-241) PDGF:Phospho-PDGFRreceptor dimer:NckPDGFC-1(235-345) N-ter PDGFA-2 fragment PDGFB(82-241) PDGFC-1 PDGF:Phospho-PDGFreceptor dimer:PI3KHeparan sulphate PDGFA-2 PDGFA-2 NCK2 PDGFB (82-190) GRB2-1 PDGFA-2 PDGFA-1 PIK3R1 PiPDGFB(82-241) p-PDGFRB homo andheterodimersRAPGEF1PDGF:Phospho-PDGFreceptor dimer:CrkPDGFB (82-190) PDGFA-2 PDGFB(82-241) PDGFA-1 Extracellular matrixligandsp21 RAS:GTPPDGFB (82-190) PDGFA-2 proPDGF-AB dimerThrombospondin DAG and IP3signalingPDGF A/B heterodimerSTAT5A PDGFB (82-190) PDGFB(1-241) p-12Y-PDGFRB PDGFA-2 BCAR1PDGFB (82-190) GDPPDGFB(82-241) N-ter PDGF-AfragmentNRAS Active PDGF dimers(AA, AB, BB)ADPPDGFC-1(23-345) p-11Y-PDGFRA PDGFA-1 PDGFB (82-190) PDGFB (82-190) p-11Y-PDGFRA PDGFA-2 KRAS PI(3,4,5)P3PDGF alpha receptor:PDGF dimersp-4Y-PLCG1PDGF:Phospho-PDGFreceptordimer:PLC-gammaSTAT5B PDGFRB RASA1 p-PDGFRB homo andheterodimersdephosphorylated atY1021PIK3R1 PDGFA-2 p-12Y-PDGFRB CRK Collagens p-11Y-PDGFRA ATPKRAS Heparan sulphate PDGF:Phospho-PDGFreceptordimer:Crk:p130Cas:C3GSOS1 NCK1 ATPPDGFA-2 PDGFRA STAT5A PDGFB(82-241) PDGFA-1 PDGFA-1 PDGFA-2 PDGFB (82-190) PDGFA-2 PDGFD(20-257) 1, 6, 12, 13, 16...291732, 36


Description

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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 186797
Reactome-version 
Reactome version: 64
Reactome Author 
Reactome Author: Garapati, Phani Vijay, Jassal, Bijay

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
101493view11:36, 1 November 2018ReactomeTeamreactome version 66
101030view21:16, 31 October 2018ReactomeTeamreactome version 65
100563view19:50, 31 October 2018ReactomeTeamreactome version 64
100111view16:35, 31 October 2018ReactomeTeamreactome version 63
99661view15:06, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99261view12:45, 31 October 2018ReactomeTeamreactome version 62
93838view13:40, 16 August 2017ReactomeTeamreactome version 61
93393view11:22, 9 August 2017ReactomeTeamreactome version 61
86479view09:19, 11 July 2016ReactomeTeamreactome version 56
83084view09:55, 18 November 2015ReactomeTeamVersion54
81405view12:56, 21 August 2015ReactomeTeamVersion53
76874view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76579view11:56, 16 July 2014ReactomeTeamFixed remaining interactions
75912view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75612view10:47, 10 June 2014ReactomeTeamReactome 48 Update
74967view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74611view08:39, 30 April 2014ReactomeTeamReactome46
45212view17:24, 7 October 2011KhanspersOntology Term : 'PDGF signaling pathway' added !
42132view21:59, 4 March 2011MaintBotAutomatic update
39942view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active PDGF dimers (AA, AB, BB)ComplexR-HSA-380760 (Reactome)
Active PDGF dimers (CC, DD)ComplexR-HSA-381939 (Reactome)
BCAR1 ProteinP56945 (Uniprot-TrEMBL)
BCAR1ProteinP56945 (Uniprot-TrEMBL)
CRK ProteinP46108 (Uniprot-TrEMBL)
CRK, CRKLComplexR-HSA-381945 (Reactome)
CRKL ProteinP46109 (Uniprot-TrEMBL)
Cleaved PDGF-B peptidesComplexR-HSA-389066 (Reactome)
Cleaved novel PDGF fragmentsComplexR-HSA-389070 (Reactome)
Collagens R-HSA-375078 (Reactome)
DAG and IP3 signalingPathwayR-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 ligandsComplexR-HSA-381946 (Reactome)
FURINProteinP09958 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GRB7ProteinQ14451 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
Heparan sulphate R-ALL-381932 (Reactome)
KRAS ProteinP01116 (Uniprot-TrEMBL)
MyrG-SRC ProteinP12931 (Uniprot-TrEMBL)
MyrG-SRCProteinP12931 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
N-ter PDGF-A fragmentComplexR-HSA-8865271 (Reactome)
N-ter PDGFA-1 fragment ProteinP04085-1 (Uniprot-TrEMBL)
N-ter PDGFA-2 fragmentProteinP04085-2 (Uniprot-TrEMBL)
N-ter PDGFA-2 fragment ProteinP04085-2 (Uniprot-TrEMBL)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1,NCK2ComplexR-HSA-381949 (Reactome)
NCK2 ProteinO43639 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
Novel PDGF precursor dimers (CC, DD)ComplexR-HSA-381942 (Reactome)
Novel PDGF precursor dimers (CC, DD)ComplexR-HSA-381947 (Reactome)
PDGF A and B chains:ECM complexComplexR-HSA-381952 (Reactome)
PDGF A and B chains

with retention

motif
ComplexR-HSA-381934 (Reactome)
PDGF A/B heterodimerComplexR-HSA-380759 (Reactome)
PDGF alpha receptor: PDGF dimersComplexR-HSA-389079 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimersComplexR-HSA-389077 (Reactome)
PDGF beta

receptor:PDGF chain

B homodimer
ComplexR-HSA-389078 (Reactome)
PDGF precursor

dimers (AA, BB,

A/B, CC, DD)
ComplexR-HSA-381936 (Reactome)
PDGF precursor

dimers (AA, BB,

A/B, CC, DD)
ComplexR-HSA-381926 (Reactome)
PDGF receptor monomerComplexR-HSA-186792 (Reactome)
PDGF:PDGF receptor dimerComplexR-HSA-186766 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:Crk:p130Cas:C3G
ComplexR-HSA-381957 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:Grb2:Sos1
ComplexR-HSA-186827 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-SRC
ComplexR-HSA-186831 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-p-Y419-SRC
ComplexR-HSA-380768 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:PLC-gamma
ComplexR-HSA-186795 (Reactome)
PDGF:Phospho-PDGF receptor dimer:CrkComplexR-HSA-381955 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Grb7ComplexR-HSA-381956 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PI3KComplexR-HSA-186789 (Reactome)
PDGF:Phospho-PDGF receptor dimer:SHP2ComplexR-HSA-186839 (Reactome)
PDGF:Phospho-PDGF receptor dimerComplexR-HSA-186811 (Reactome)
PDGF:Phospho-PDGFR receptor dimer:NckComplexR-HSA-381954 (Reactome)
PDGF:p-PDGFR dimer:p-PLCgammaComplexR-HSA-1524184 (Reactome)
PDGF:phospho-PDGF receptor dimer:STATComplexR-HSA-380766 (Reactome)
PDGFA-1 ProteinP04085-1 (Uniprot-TrEMBL)
PDGFA-1(1-211) ProteinP04085-1 (Uniprot-TrEMBL)
PDGFA-2 ProteinP04085-2 (Uniprot-TrEMBL)
PDGFB (82-190) ProteinP01127 (Uniprot-TrEMBL)
PDGFB(1-241) ProteinP01127 (Uniprot-TrEMBL)
PDGFB(1-81) ProteinP01127 (Uniprot-TrEMBL)
PDGFB(191-241) ProteinP01127 (Uniprot-TrEMBL)
PDGFB(82-241) ProteinP01127 (Uniprot-TrEMBL)
PDGFC-1 ProteinQ9NRA1-1 (Uniprot-TrEMBL)
PDGFC-1(23-345) ProteinQ9NRA1-1 (Uniprot-TrEMBL)
PDGFC-1(235-345) ProteinQ9NRA1-1 (Uniprot-TrEMBL)
PDGFC-1(24-234) ProteinQ9NRA1-1 (Uniprot-TrEMBL)
PDGFD(1-370) ProteinQ9GZP0 (Uniprot-TrEMBL)
PDGFD(19-370) ProteinQ9GZP0 (Uniprot-TrEMBL)
PDGFD(20-257) ProteinQ9GZP0 (Uniprot-TrEMBL)
PDGFD(258-370) ProteinQ9GZP0 (Uniprot-TrEMBL)
PDGFRA ProteinP16234 (Uniprot-TrEMBL)
PDGFRB ProteinP09619 (Uniprot-TrEMBL)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3KComplexR-HSA-74693 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-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.
PLAT(36-562) ProteinP00750 (Uniprot-TrEMBL)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PLG(20-580) ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810) ProteinP00747 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN12ProteinQ05209 (Uniprot-TrEMBL)
Phospho PDGF

alpha-beta dimer:PDGF AB or BB

dimers
ComplexR-HSA-389076 (Reactome)
Phospho PDGF alpha

receptor:PDGF

dimers
ComplexR-HSA-389073 (Reactome)
Phospho PDGF beta

receptor: PDGF

chain B homodimer
ComplexR-HSA-389074 (Reactome)
Phospho-beta

receptor

homodimer:GAP
ComplexR-HSA-186830 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayR-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 ProteinQ13905 (Uniprot-TrEMBL)
RAPGEF1ProteinQ13905 (Uniprot-TrEMBL)
RASA1 ProteinP20936 (Uniprot-TrEMBL)
RASA1ProteinP20936 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SPP1 ProteinP10451 (Uniprot-TrEMBL)
STAT family membersComplexR-HSA-380756 (Reactome)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STAT6 ProteinP42226 (Uniprot-TrEMBL)
Thrombospondin R-HSA-684997 (Reactome)
active PDGF-AA dimerComplexR-HSA-380761 (Reactome)
active PDGF-BB dimerComplexR-HSA-184206 (Reactome)
p-11Y-PDGFRA ProteinP16234 (Uniprot-TrEMBL)
p-11Y-PDGFRB ProteinP09619 (Uniprot-TrEMBL)
p-12Y-PDGFRB ProteinP09619 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-PDGFRB homo and

heterodimers dephosphorylated at

Y1021
ComplexR-HSA-8864045 (Reactome)
p-PDGFRB homo and heterodimersComplexR-HSA-8864037 (Reactome)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
proPDGF-AA dimerComplexR-HSA-380749 (Reactome)
proPDGF-AB dimerComplexR-HSA-380751 (Reactome)
proPDGF-BB dimerComplexR-HSA-380748 (Reactome)
serine-type

endopeptidases involved in novel

PDGF processing
ComplexR-HSA-381937 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-186786 (Reactome)
ADPArrowR-HSA-186800 (Reactome)
ADPArrowR-HSA-380780 (Reactome)
ADPArrowR-HSA-389083 (Reactome)
ADPArrowR-HSA-389086 (Reactome)
ATPR-HSA-186786 (Reactome)
ATPR-HSA-186800 (Reactome)
ATPR-HSA-380780 (Reactome)
ATPR-HSA-389083 (Reactome)
ATPR-HSA-389086 (Reactome)
Active PDGF dimers (AA, AB, BB)R-HSA-186773 (Reactome)
Active PDGF dimers (CC, DD)ArrowR-HSA-382061 (Reactome)
BCAR1R-HSA-382052 (Reactome)
CRK, CRKLR-HSA-382056 (Reactome)
Cleaved PDGF-B peptidesArrowR-HSA-8865275 (Reactome)
Cleaved PDGF-B peptidesArrowR-HSA-8865276 (Reactome)
Cleaved novel PDGF fragmentsArrowR-HSA-382061 (Reactome)
Extracellular matrix ligandsR-HSA-382054 (Reactome)
FURINmim-catalysisR-HSA-186785 (Reactome)
FURINmim-catalysisR-HSA-8865275 (Reactome)
FURINmim-catalysisR-HSA-8865276 (Reactome)
GDPArrowR-HSA-186834 (Reactome)
GRB2-1:SOS1R-HSA-186826 (Reactome)
GRB7R-HSA-382055 (Reactome)
GTPR-HSA-186834 (Reactome)
H2OR-HSA-8864036 (Reactome)
MyrG-SRCR-HSA-186819 (Reactome)
N-ter PDGF-A fragmentArrowR-HSA-186785 (Reactome)
N-ter PDGFA-2 fragmentArrowR-HSA-8865276 (Reactome)
NCK1,NCK2R-HSA-382058 (Reactome)
Novel PDGF precursor dimers (CC, DD)ArrowR-HSA-382057 (Reactome)
Novel PDGF precursor dimers (CC, DD)R-HSA-382057 (Reactome)
Novel PDGF precursor dimers (CC, DD)R-HSA-382061 (Reactome)
PDGF A and B chains:ECM complexArrowR-HSA-382054 (Reactome)
PDGF A and B chains

with retention

motif
R-HSA-382054 (Reactome)
PDGF A/B heterodimerArrowR-HSA-8865276 (Reactome)
PDGF alpha receptor: PDGF dimersR-HSA-389083 (Reactome)
PDGF alpha receptor: PDGF dimersmim-catalysisR-HSA-389083 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimersR-HSA-389086 (Reactome)
PDGF alpha/beta:PDGF AB and BB dimersmim-catalysisR-HSA-389086 (Reactome)
PDGF beta

receptor:PDGF chain

B homodimer
R-HSA-186786 (Reactome)
PDGF beta

receptor:PDGF chain

B homodimer
mim-catalysisR-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)
ArrowR-HSA-382053 (Reactome)
PDGF receptor monomerR-HSA-186773 (Reactome)
PDGF:PDGF receptor dimerArrowR-HSA-186773 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:Crk:p130Cas:C3G
ArrowR-HSA-382052 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:Grb2:Sos1
ArrowR-HSA-186826 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:Grb2:Sos1
mim-catalysisR-HSA-186834 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-SRC
ArrowR-HSA-186819 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-SRC
R-HSA-380780 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-SRC
mim-catalysisR-HSA-380780 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:MyrG-p-Y419-SRC
ArrowR-HSA-380780 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:PLC-gamma
ArrowR-HSA-186765 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:PLC-gamma
R-HSA-1524186 (Reactome)
PDGF:Phospho-PDGF

receptor

dimer:PLC-gamma
mim-catalysisR-HSA-1524186 (Reactome)
PDGF:Phospho-PDGF receptor dimer:CrkArrowR-HSA-382056 (Reactome)
PDGF:Phospho-PDGF receptor dimer:CrkR-HSA-382052 (Reactome)
PDGF:Phospho-PDGF receptor dimer:Grb7ArrowR-HSA-382055 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PI3KArrowR-HSA-186780 (Reactome)
PDGF:Phospho-PDGF receptor dimer:PI3Kmim-catalysisR-HSA-186800 (Reactome)
PDGF:Phospho-PDGF receptor dimer:SHP2ArrowR-HSA-186778 (Reactome)
PDGF:Phospho-PDGF receptor dimerArrowR-HSA-1524182 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-186765 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-186778 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-186780 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-186819 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-186826 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-380782 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-382055 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-382056 (Reactome)
PDGF:Phospho-PDGF receptor dimerR-HSA-382058 (Reactome)
PDGF:Phospho-PDGFR receptor dimer:NckArrowR-HSA-382058 (Reactome)
PDGF:p-PDGFR dimer:p-PLCgammaArrowR-HSA-1524186 (Reactome)
PDGF:p-PDGFR dimer:p-PLCgammaR-HSA-1524182 (Reactome)
PDGF:phospho-PDGF receptor dimer:STATArrowR-HSA-380782 (Reactome)
PI(3,4,5)P3ArrowR-HSA-186800 (Reactome)
PI(4,5)P2R-HSA-186800 (Reactome)
PI3KR-HSA-186780 (Reactome)
PLCG1R-HSA-186765 (Reactome)
PTPN11R-HSA-186778 (Reactome)
PTPN12mim-catalysisR-HSA-8864036 (Reactome)
Phospho PDGF

alpha-beta dimer:PDGF AB or BB

dimers
ArrowR-HSA-389086 (Reactome)
Phospho PDGF alpha

receptor:PDGF

dimers
ArrowR-HSA-389083 (Reactome)
Phospho PDGF beta

receptor: PDGF

chain B homodimer
ArrowR-HSA-186786 (Reactome)
Phospho PDGF beta

receptor: PDGF

chain B homodimer
R-HSA-186798 (Reactome)
Phospho-beta

receptor

homodimer:GAP
ArrowR-HSA-186798 (Reactome)
PiArrowR-HSA-8864036 (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. 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).
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 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.
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
R-HSA-8864036 (Reactome) 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).
R-HSA-8865275 (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. 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).
R-HSA-8865276 (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. 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).
RAPGEF1R-HSA-382052 (Reactome)
RASA1R-HSA-186798 (Reactome)
STAT family membersR-HSA-380782 (Reactome)
active PDGF-AA dimerArrowR-HSA-186785 (Reactome)
active PDGF-BB dimerArrowR-HSA-8865275 (Reactome)
p-4Y-PLCG1ArrowR-HSA-1524182 (Reactome)
p-PDGFRB homo and

heterodimers dephosphorylated at

Y1021
ArrowR-HSA-8864036 (Reactome)
p-PDGFRB homo and heterodimersR-HSA-8864036 (Reactome)
p21 RAS:GDPR-HSA-186834 (Reactome)
p21 RAS:GTPArrowR-HSA-186834 (Reactome)
proPDGF-AA dimerR-HSA-186785 (Reactome)
proPDGF-AB dimerR-HSA-8865276 (Reactome)
proPDGF-BB dimerR-HSA-8865275 (Reactome)
serine-type

endopeptidases involved in novel

PDGF processing
mim-catalysisR-HSA-382061 (Reactome)
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