Editing Platelet-derived growth factor (section)

== Mechanisms ==

The [[Receptor (biochemistry)|receptor]] for PDGF, '''PDGFR''' is classified as a [[receptor tyrosine kinase]] (RTK), a type of [[plasma membrane|cell surface]] receptor.  Two types of PDGFRs have been identified: alpha-type and beta-type PDGFRs.<ref>{{cite journal |vauthors=Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J, Aaronson S | title = Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes | journal = Science | volume = 243 | issue = 4892 | pages = 800–804 | year = 1989 | pmid = 2536956 | doi = 10.1126/science.2536956 | bibcode = 1989Sci...243..800M | url = https://zenodo.org/record/1231010 }}</ref> The alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB, whereas the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB.<ref>{{cite journal | vauthors = Heidaran MA, Pierce JH, Yu JC, Lombardi D, Artrip JE, Fleming TP, Thomason A, Aaronson SA | title = Role of alpha beta receptor heterodimer formation in beta platelet-derived growth factor (PDGF) receptor activation by PDGF-AB | journal = J. Biol. Chem. | volume = 266 | issue = 30 | pages = 20232–7 | date = 25 October 1991 | doi = 10.1016/S0021-9258(18)54914-0 | pmid = 1657917 | doi-access = free }}</ref>
PDGF binds to the PDGFR ligand binding pocket located within the second and third immunoglobulin domains.<ref>{{cite journal | vauthors = Heidaran MA, Pierce JH, Jensen RA, Matsui T, Aaronson SA | title = Chimeric alpha- and beta-platelet-derived growth factor (PDGF) receptors define three immunoglobulin-like domains of the alpha-PDGF receptor that determine PDGF-AA binding specificity | journal = J. Biol. Chem. | volume = 265 | issue = 31 | pages = 18741–18744 | date = 5 November 1990 | doi = 10.1016/S0021-9258(17)30572-0 | pmid = 2172231 | doi-access = free }}</ref> Upon activation by PDGF, these receptors dimerise, and are "switched on" by auto-[[phosphorylation]] of several sites on their [[cytosol]]ic domains, which serve to mediate binding of cofactors and subsequently activate [[signal transduction]], for example, through the [[Phosphoinositide 3-kinase|PI3K]] pathway or through [[reactive oxygen species (ROS)]]-mediated activation of the [[STAT3]] pathway.<ref name="pmid24165129">{{cite journal |vauthors=Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH | title = 12/15-Lipoxygenase Contributes to Platelet-derived Growth Factor-induced Activation of Signal Transducer and Activator of Transcription 3 | journal = J. Biol. Chem. | volume = 288 | issue = 49 | pages = 35592–35603 | date = December 2013 | pmid = 24165129 | pmc = 3853304 | doi = 10.1074/jbc.M113.489013 | doi-access = free }}</ref> Downstream effects of this include regulation of [[gene expression]] and the [[cell cycle]].
The role of PI3K has been investigated by several laboratories. Accumulating data suggests that, while this molecule is, in general, part of growth signaling complex, it plays a more profound role in controlling cell migration.<ref>{{cite journal |vauthors=Yu JC, Li W, Wang LM, Uren A, Pierce JH, Heidaran MA | title = Differential requirement of a motif within the carboxyl-terminal domain of alpha-platelet-derived growth factor (alpha PDGF) receptor for PDGF focus forming activity chemotaxis, or growth | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7033–7036 | year = 1995 | pmid = 7706238 | doi = 10.1074/jbc.270.13.7033 | doi-access = free }}</ref>
The different ligand isoforms have variable affinities for the receptor isoforms, and the receptor isoforms may variably form hetero- or homo- dimers.  This leads to specificity of downstream signaling.  It has been shown that the [[sis oncogene]] is derived from the PDGF B-chain [[gene]]. PDGF-BB is the highest-affinity ligand for the PDGFR-beta; PDGFR-beta is a key marker of hepatic stellate cell activation in the process of [[fibrogenesis]].{{Citation needed|date=April 2007}}