血小板由来成長因子受容体、血小板由来成長因子レセプター、PDGF受容体、PDGFレセプター

関: platelet-derived growth factor receptor

WordNet

a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

=sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/11/13 16:13:57」(JST)

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Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer.^[2] There are two forms of the PDGF-R, alpha and beta each encoded by a different gene.^[3] Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.^[4]

Mechanism of action[edit]

The PDGF family consists of PDGF-A, -B, -C and -D, which form either homo- or heterodimers (PDGF-AA, -AB, -BB, -CC, -DD). The four PDGFs are inactive in their monomeric forms. The PDGFs bind to the protein tyrosine kinase receptors PDGF receptor-α and -β. These two receptor isoforms dimerize upon binding the PDGF dimer, leading to three possible receptor combinations, namely -αα, -ββ and -αβ. The extracellular region of the receptor consists of five immunoglobulin-like domains while the intracellular part is a tyrosine kinase domain. The ligand-binding sites of the receptors are located to the three first immunoglobulin-like domains. PDGF-CC specifically interacts with PDGFR-αα and -αβ, but not with -ββ, and thereby resembles PDGF-AB. PDGF-DD binds to PDGFR-ββ with high affinity, and to PDGFR-αβ to a markedly lower extent and is therefore regarded as PDGFR-ββ specific. PDGF-AA binds only to PDGFR-αα, while PDGF-BB is the only PDGF that can bind all three receptor combinations with high affinity.^[5]

Dimerization is a prerequisite for the activation of the kinase. Kinase activation is visualized as tyrosine phosphorylation of the receptor molecules, which occurs between the dimerized receptor molecules (transphosphorylation). In conjunction with dimerization and kinase activation, the receptor molecules undergo conformational changes, which allow a basal kinase activity to phosphorylate a critical tyrosine residue, thereby "unlocking" the kinase, leading to full enzymatic activity directed toward other tyrosine residues in the receptor molecules as well as other substrates for the kinase. Expression of both receptors and each of the four PDGFs is under independent control, giving the PDGF/PDGFR system a high flexibility. Different cell types vary greatly in the ratio of PDGF isoforms and PDGFRs expressed. Different external stimuli such as inflammation, embryonic development or differentiation modulate cellular receptor expression allowing binding of some PDGFs but not others. Additionally, some cells display only one of the PDGFR isoforms while other cells express both isoforms, simultaneously or separately.

Interaction with signal transduction molecules[edit]

Tyrosine phosphorylation sites in growth factor receptors serve two major purposes: to control the state of activity of the kinase and to create binding sites for downstream signal transduction molecules, which in many cases also are substrates for the kinase. The second part of the tyrosine kinase domain in the PDGFβ receptor is phosphorylated at Tyr-857, and mutant receptors carrying phenylalanine at this position have reduced kinase activity. Tyr-857 has therefore been assigned a role in positive regulation of kinase activity.^[6] Sites of tyrosine phosphorylation involved in binding signal transduction molecules have been identified in the juxtamembrane domain, the kinase insert, and in the C-terminal tail in the PDGFβ receptor. The phosphorylated tyrosine residue and in general three adjacent C-terminal amino acid residues form specific binding sites for signal transduction molecules. Binding to these sites involves a common conserved stretches, denoted the Src homology (SH) 2 domain and/or Phosphotyrosine Binding Domains (PTB). The specificity of these interactions appears to be very high, since mutant receptors carrying phenylalanine residues in one or several of the different phosphorylation sites generally lack the capacity to bind the targeted signal transduction molecule. The signal transduction molecules are either equipped with different enzymatic activities, or they are adaptor molecules, which in some but not all cases are found in complexes with subunits that carry a catalytic activity. Upon interaction with the activated receptor, the catalytic activities become up-regulated, through tyrosine phosphorylation or other mechanisms, generating a signal that may be unique for each type of signal transduction molecule.

Examination of the different signalling cascades, induced by RTKs, established Ras/mitogen-activated protein kinase (MAPK),PI-3 kinase and phospholipase-γ (PLCγ) pathways as key downstream mediators of the PDGFR signalling.^[7]^[8] In addition, reactive oxygen species (ROS)-dependent STAT3 activation has been established to be a key downstream mediator of PDGFR signalling in vascular smooth muscle cells.^[9]

MAPK pathway[edit]

The adaptor protein Grb2 forms a complex with Sos by the Grb2 SH3 domain. Grb2 (or) the Grb2/Sos complex is recruited to the membrane by the Grb2 SH2 domain binding to activated PDGFR-bound SHP2 (Also known as PTPN11, a cytosolic PTP), thereby allowing interaction with Ras and the exchange of GDP for GTP on Ras. Whereas the interaction between Grb2 and PDGFR occurs through interaction with the SHP2 protein, Grb2 binds to activated EGFR through Shc, another adaptor protein that forms a complex with many receptors via its PTB domain.^[10] Once activated, Ras interacts with several proteins, namely Raf. Activated Raf stimulates MAPK-kinase (MAPKK or MEK) by phosphorylating a Ser residue in its activation loop. MAPKK then phosphorylates MAPK (ERK1/2) on T and Y residues at the activation-loop leading to its activation. Activated MAPK phosphorylates a variety of cytoplasmic substrates, as well as transcription factors, when translocated into the nucleus. MAPK family members have been found to regulate various biological functions by phosphorylation of particular target molecules (such as transcription factors, other kinases etc.) located in cell membrane, cytoplasm and nucleus, and thus contribute to the regulation of different cellular processes such as cell proliferation, differentiation, apoptosis and immunoresponses.

PI3K pathway[edit]

The class IA phospholipid kinase, PI-3 kinase, is activated by the majority of RTKs. Similarly to other SH2 domain-containing proteins, PI-3 kinase forms a complex with PY sites on activated receptors. The main function of PI3K activation is the generation of PIP3, which functions as a second messenger to activate downstream tyrosine kinases Btk and Itk, the Ser/Thr kinases PDK1 and Akt (PKB). The major biological functions of Akt activation can be classified into three categories – survival,proliferation and cell growth. Akt is also known to be implicated in several cancers, particularly breast. PLCγ is immediately recruited by an activated RTK through the binding of its SH2 domains to phosphotyrosine sites of the receptor. After activation, PLCγ hydrolyses its substrate PtdIns(4,5)P2 and forms two second messengers, diacylglycerol and Ins(1,4,5)P3. Ins(1,4,5)P3 stimulates the release of Ca 2+ from intracellular supplies. Ca 2+ then binds to calmodulin, which subsequently activates a family of calmodulindependent protein kinases (CamKs). In addition, both diacylglycerol and Ca 2+ activate members of the PKC family. The second messengers generated by PtdIns(4,5)P2 hydrolysis stimulate a variety of intracellular processes such as proliferation,angiogenesis, cell motility.

References[edit]

^ PDB 3MJG; Shima AHR, Liua H, Fociaa PJ, Chena X, Linb PC, He X. (2010). "Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex". PNAS 107 (25): 11307–12. doi:10.1073/pnas.1000806107. PMC 2895058. PMID 20534510. Unknown parameter |no= ignored (help); rendered using PyMOL.
^ Williams LT (March 1989). "Signal transduction by the platelet-derived growth factor receptor". Science 243 (4898): 1564–70. doi:10.1126/science.2538922. PMID 2538922.
^ Heldin CH, Westermark B (April 1989). "Platelet-derived growth factor: three isoforms and two receptor types". Trends Genet. 5 (4): 108–11. doi:10.1016/0168-9525(89)90040-1. PMID 2543106.
^ Heldin CH, Ostman A, Eriksson A, Siegbahn A, Claesson-Welsh L, Westermark B (March 1992). "Platelet-derived growth factor: isoform-specific signalling via heterodimeric or homodimeric receptor complexes". Kidney Int. 41 (3): 571–4. doi:10.1038/ki.1992.84. PMID 1315403.
^ Cao Y, Cao R, Hedlund EM (July 2008). "R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways.". J Mol Med (Berl) 86 (7): 785–9. doi:10.1007/s00109-008-0337-z. PMID 18392794.
^ Kazlauskas A, Cooper JA (September 1989). "Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins.". Cell 58 (6): 1121–33. doi:10.1016/0092-8674(89)90510-2. PMID 2550144.
^ Valius M, Kazlauskas A (April 1993). "Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal.". Cell 73 (2): 321–34. doi:10.1016/0092-8674(93)90232-F. PMID 7682895.
^ Montmayeur JP, Valius M, Vandenheede J, Kazlauskas A. (December 1997). "The platelet-derived growth factor beta receptor triggers multiple cytoplasmic signaling cascades that arrive at the nucleus as distinguishable inputs.". J Biol Chem 272 (51): 332670–8. doi:10.1074/jbc.272.51.32670. PMID 9405485.
^ Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH. 12/15-Lipoxygenase contributes toPlatelet-Derived Growth Factor- Induced Activation of Signal Transducer and Activator of Transcription 3. J Biol Chem. 2013 Oct 28. PubMed PMID: 24165129.
^ Schlessinger, J. SH2/SH3 Signaling Proteins. Curr. Op. Gen. Dev. 1994, 4(1):25-30.

External links[edit]

Platelet-Derived Growth Factor Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)

http://angiogenesis.amgen.com

UpToDate Contents

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English Journal

The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin.

Fan Y, Du W, He B, Fu F, Yuan L, Wu H, Dai W, Zhang H, Wang X, Wang J, Zhang X, Zhang Q.SourceState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Biomaterials.Biomaterials.2013 Mar;34(9):2277-88. doi: 10.1016/j.biomaterials.2012.12.012. Epub 2013 Jan 4.
Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue and it constitutes a great obstacle for the delivery of chemodrugs, which makes it a potential target for cancer therapy. In this study, imatinib, a molecular targeting drug, was loaded in sterically stabilized lipo
PMID 23290525

Melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia-reperfusion injury.

Yip HK, Chang YC, Wallace CG, Chang LT, Tsai TH, Chen YL, Chang HW, Leu S, Zhen YY, Tsai CY, Yeh KH, Sun CK, Yen CH.SourceDivision of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Journal of pineal research.J Pineal Res.2013 Mar;54(2):207-21. doi: 10.1111/jpi.12020. Epub 2012 Oct 30.
This study investigated whether melatonin-treated adipose-derived mesenchymal stem cells (ADMSC) offered superior protection against acute lung ischemia-reperfusion (IR) injury. Adult male Sprague-Dawley rats (n = 30) were randomized equally into five groups: sham controls, lung IR-saline, lung IR
PMID 23110436

STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer.

Peña C, Céspedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, Hägglöf C, Birgisson H, Bojmar L, Jirström K, Sandström P, Olsson E, Veerla S, Gallardo A, Sjöblom T, Chang AC, Reddel RR, Mangues R, Augsten M, Ostman A.SourceAuthors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Grupo de Oncogenesis y Antitumorales, Institute of Biomedical Research (IIB Sant Pau) and Network Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain; Department of Immunology, Genetics and Pathology and Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Uppsala; Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping; Departments of Clinical Sciences and Clinical Genetics, Lund University, Lund, Sweden; and Children's Medical Research Institute and Sydney Medical School, University of Sydney, Sydney, Australia.
Cancer research.Cancer Res.2013 Feb 15;73(4):1287-1297. Epub 2012 Dec 14.
Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understo
PMID 23243022

Japanese Journal

Screening of Therapeutic Targets for Canine Mast Cell Tumors from a Variety of Kinase Molecules

TAKEUCHI Yoshinori,FUJINO Yasuhito,WATANABE Manabu,NAKAGAWA Takayuki,OHNO Koichi,SASAKI Nobuo,SUGANO Sumio,TSUJIMOTO Hajime
Journal of Veterinary Medical Science advpub(0), 1105280532, 2011
… To identify the novel candidate therapeutic targets for canine MCT, the mRNA expression and phosphorylation statuses of several receptor or non-receptor kinases as well as the inhibitory effect of 95 specific inhibitors on the growth were assessed in three canine MCT cell lines (HRMC, VIMC1 and CMMC1). … Only three inhibitors such as SB218078 (for Chk1), PDGF RTK inhibitor IV (for PDGFR) and radicicol (for Hsp90) suppressed the growth of all three cell lines. …
NAID 130000868200

Inhibitory Effects of Docetaxel on Platelet-Derived Growth Factor (PDGF)-BB–Induced Proliferation of Vascular Smooth Muscle Cells Through Blocking PDGF-Receptor β Phosphorylation

Park Eun Seok,Yoo Jae-Myung,Lim Yong,Tudev Munkhtsetseg,Yoo Hwan-Soo,Hong Jin Tae,Yun Yeo-Pyo
Journal of Pharmacological Sciences 116(2), 204-213, 2011
… Docetaxel at 10, 20 and 40 μM significantly inhibited both the proliferation and the DNA synthesis of fetal bovine serum (FBS)- and platelet-derived growth factor (PDGF)-BB–stimulated VSMCs in a concentration-dependent manner. … In accordance with these findings, docetaxel blocked the FBS- and PDGF-BB–induced progression of synchronized cells through the G0/G1 phase of the cell cycle. …
NAID 130000835865

Related Pictures

★リンクテーブル★

リンク元	「血小板由来成長因子受容体」「血小板由来成長因子レセプター」「platelet-derived growth factor receptor」「PDGF受容体」「PDGFレセプター」
関連記事	「PD」「PDGF」

「血小板由来成長因子受容体」

platelet-derived growth factor receptor, beta polypeptide
	; Ribbon image of two molecules of human PDGF receptor beta (yellow and magenta) in complex with dimeric PDGF-B (cyan and green).
Identifiers
Symbol	PDGFRB
Alt. symbols	PDGFR
Entrez	5159
HUGO	8804
OMIM	173410
RefSeq	NM_002609
UniProt	P09619
Other data
Locus	Chr. 5 q31-q32

platelet-derived growth factor receptor, alpha polypeptide
Identifiers
Symbol	PDGFRA
Entrez	5156
HUGO	8803
OMIM	173490
RefSeq	NM_006206
UniProt	P16234
Other data
Locus	Chr. 4 q12

　　[★]

英: platelet-derived growth factor receptor、PDGF receptor
関: PDGF受容体、血小板由来成長因子レセプター、PDGFレセプター、血小板由来増殖因子レセプター、血小板由来増殖因子受容体

同受容体のチロシンキナーゼがイマチニブの標的となる。

BCR-ALB/C-KIT/PDGFR阻害薬

「血小板由来成長因子レセプター」

　　[★]

英: platelet-derived growth factor receptor、PDGF receptor
関: PDGF受容体、PDGFレセプター、血小板由来成長因子受容体、血小板由来増殖因子レセプター、血小板由来増殖因子受容体

「platelet-derived growth factor receptor」

　　[★]

血小板由来増殖因子受容体、血小板由来増殖因子レセプター、血小板由来成長因子受容体、血小板由来成長因子レセプター

関: PDGF receptor

「PDGF受容体」

　　[★]

英: PDGF receptor
関: 血小板由来成長因子レセプター、PDGFレセプター、血小板由来成長因子受容体、血小板由来増殖因子レセプター

「PDGFレセプター」

　　[★]

英: PDGF receptor
関: PDGF受容体、血小板由来成長因子レセプター、血小板由来成長因子受容体

「PD」

　　[★]

「PDGF」

　　[★] 血小板由来成長因子

同: platelel-derived growth factor

同: platelet-derived growth factor

[3MJG-1] PDB 3MJG; Shima AHR, Liua H, Fociaa PJ, Chena X, Linb PC, He X. (2010). "Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex". PNAS 107 (25): 11307–12. doi:10.1073/pnas.1000806107. PMC 2895058. PMID 20534510. Unknown parameter |no= ignored (help); rendered using PyMOL.

[pmid2538922-2] Williams LT (March 1989). "Signal transduction by the platelet-derived growth factor receptor". Science 243 (4898): 1564–70. doi:10.1126/science.2538922. PMID 2538922.

[pmid2543106-3] Heldin CH, Westermark B (April 1989). "Platelet-derived growth factor: three isoforms and two receptor types". Trends Genet. 5 (4): 108–11. doi:10.1016/0168-9525(89)90040-1. PMID 2543106.

[pmid1315403-4] Heldin CH, Ostman A, Eriksson A, Siegbahn A, Claesson-Welsh L, Westermark B (March 1992). "Platelet-derived growth factor: isoform-specific signalling via heterodimeric or homodimeric receptor complexes". Kidney Int. 41 (3): 571–4. doi:10.1038/ki.1992.84. PMID 1315403.

[pmid18392794-5] Cao Y, Cao R, Hedlund EM (July 2008). "R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways.". J Mol Med (Berl) 86 (7): 785–9. doi:10.1007/s00109-008-0337-z. PMID 18392794.

[pmid2550144-6] Kazlauskas A, Cooper JA (September 1989). "Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins.". Cell 58 (6): 1121–33. doi:10.1016/0092-8674(89)90510-2. PMID 2550144.

[pmid7682895-7] Valius M, Kazlauskas A (April 1993). "Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal.". Cell 73 (2): 321–34. doi:10.1016/0092-8674(93)90232-F. PMID 7682895.

[pmid9405485-8] Montmayeur JP, Valius M, Vandenheede J, Kazlauskas A. (December 1997). "The platelet-derived growth factor beta receptor triggers multiple cytoplasmic signaling cascades that arrive at the nucleus as distinguishable inputs.". J Biol Chem 272 (51): 332670–8. doi:10.1074/jbc.272.51.32670. PMID 9405485.

[9] Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH. 12/15-Lipoxygenase contributes toPlatelet-Derived Growth Factor- Induced Activation of Signal Transducer and Activator of Transcription 3. J Biol Chem. 2013 Oct 28. PubMed PMID: 24165129.

[PMID_8193536-10] Schlessinger, J. SH2/SH3 Signaling Proteins. Curr. Op. Gen. Dev. 1994, 4(1):25-30.

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PDGF receptor