血小板衍生生長因子
血小板衍生生長因子（Platelet-derived growth factor，PDGF）為一種生長因子，可以調控細胞的生長和分化，且在血管新生上扮演重要角色。未控制的血管新生常常導致癌症。在化學上PDGF為醣蛋白二聚體，且有A和B兩種不同形式，可組合為AA、AB和BB等結構。
| 血小板衍生生長因子（PDGF） | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 | |||||||||
| 鑑定 | |||||||||
| 標誌 | PDGF | ||||||||
| Pfam | PF00341（旧版） | ||||||||
| InterPro | IPR000072 | ||||||||
| PROSITE | PDOC00222 | ||||||||
| SCOP | 1pdg / SUPFAM | ||||||||
| |||||||||
PDGF[1][2]是一種有效的间充质細胞丝裂原，包含纖維母細胞、平滑肌、神經膠細胞。在小鼠和人类中，PDGF信号网络都包括四種配体：PDGFA 到 PDGFAD，与两个受体:PDGFRA和PDGFRB。所有PDGF都表达到胞外，并通过二硫键连接形成同元二聚体，但只有PDGFA和B可以形成有功能的异元二聚体。
PDGF在被合成出來之後，會先貯存在血小板中的α顆粒當中[3]，直到受到刺激後才釋放出來。另外，平滑肌細胞、活化的巨噬細胞，和上皮細胞等多種細胞也會製造PDGF[4]。
分類 编辑
PDGF擁有五種亞型
There are five different isoforms of PDGF that activate cellular response through two different receptors. Known ligands include A (PDGFA), B (PDGFB), C (PDGFC), and D (PDGFD), and an AB heterodimer and receptors alpha (PDGFRA) and beta (PDGFRB). PDGF has few other members of the family, for example VEGF sub-family.
機制 编辑
The receptor for PDGF, PDGFR is classified as a receptor tyrosine kinase (RTK), a type of cell surface receptor. Two types of PDGFRs have been identified: alpha-type and beta-type PDGFRs.[5] 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.[6] PDGF binds to the PDGFR ligand binding pocket located within the second and third immunoglobulin domains.[7] Upon activation by PDGF, these receptors dimerise, and are "switched on" by auto-phosphorylation of several sites on their cytosolic domains, which serve to mediate binding of cofactors and subsequently activate signal transduction, for example, through the PI3K pathway or through reactive oxygen species (ROS)-mediated activation of the STAT3 pathway.[8] 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.[9] 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.[來源請求]
功能 编辑
PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During later maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal.[10] Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C)[11][12] which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.[13]
PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.[14] Over-expression of PDGF has been linked to several diseases such as atherosclerosis, fibrotic disorders and malignancies. Synthesis occurs due to external stimuli such as thrombin, low oxygen tension, or other cytokines and growth factors.[15]
PDGF is a required element in cellular division for fibroblasts, a type of connective tissue cell that is especially prevalent in wound healing.[15] In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide.[16] It has been shown that in monocytes-macrophages and fibroblasts, exogenously administered PDGF stimulates chemotaxis, proliferation, and gene expression and significantly augmented the influx of inflammatory cells and fibroblasts, accelerating extracellular matrix and collagen formation and thus reducing the time for the healing process to occur.[17]
In terms of osteogenic differentiation of mesenchymal stem cells, comparing PDGF to epidermal growth factor (EGF), which is also implicated in stimulating cell growth, proliferation, and differentiation,[18] MSCs were shown to have stronger osteogenic differentiation into bone-forming cells when stimulated by epidermal growth factor (EGF) versus PDGF. However, comparing the signaling pathways between them reveals that the PI3K pathway is exclusively activated by PDGF, with EGF having no effect. Chemically inhibiting the PI3K pathway in PDGF-stimulated cells negates the differential effect between the two growth factors, and actually gives PDGF an edge in osteogenic differentiation.[18] Wortmannin is a PI3K-specific inhibitor, and treatment of cells with Wortmannin in combination with PDGF resulted in enhanced osteoblast differentiation compared to just PDGF alone, as well as compared to EGF.[18] These results indicate that the addition of Wortmannin can significantly increase the response of cells into an osteogenic lineage in the presence of PDGF, and thus might reduce the need for higher concentrations of PDGF or other growth factors, making PDGF a more viable growth factor for osteogenic differentiation than other, more expensive growth factors currently used in the field such as BMP2.[19]
PDGF is also known to maintain proliferation of oligodendrocyte progenitor cells.[20][21] It has also been shown that fibroblast growth factor (FGF) activates a signaling pathway that positively regulates the PDGF receptors in oligodendrocyte progenitor cells.[22]
歷史 编辑
PDGF是第一种被鉴定的生长因子[23]，引领了许多生长因子信号通路的研究[來源請求]。
藥物 编辑
Recombinant PDGF is used to help heal chronic ulcers and in orthopedic surgery and periodontistry to treat bone loss.[24]
研究 编辑
Like many other growth factors that have been linked to disease, PDGF and its receptors have provided a market for receptor antagonists to treat disease. Such antagonists include (but are not limited to) specific antibodies that target the molecule of interest, which act only in a neutralizing manner.[25]
The "c-Sis" oncogene is derived from PDGF.[21][26]
Age related downregulation of the PDGF receptor on islet beta cells has been demonstrated to prevent islet beta cell proliferation in both animal and human cells and its re-expression triggered beta cell proliferation and corrected glucose regulation via insulin secretion.[27][28]
A non-viral PDGF "bio patch" can regenerate missing or damaged bone by delivering DNA in a nano-sized particle directly into cells via genes. Repairing bone fractures, fixing craniofacial defects and improving dental implants are among potential uses. The patch employs a collagen platform seeded with particles containing the genes needed for producing bone. In experiments, it new bone fully covered skull wounds in test animals and stimulated growth in human bone marrow stromal cells.[29][30]
PDGF家族 编辑
Human genes encoding proteins that belong to the platelet-derived growth factor family include:
參見 编辑
- Platelet-activating factor
- Platelet-derived growth factor receptor
- atheroma platelet involvement in smooth muscle proliferation
- Withaferin A potent inhibitor of angiogenesis
參考文獻 编辑
- ^ Hannink M, Donoghue DJ. Structure and function of platelet-derived growth factor (PDGF) and related proteins. Biochim. Biophys. Acta. 1989, 989 (1): 1–10. PMID 2546599. doi:10.1016/0304-419x(89)90031-0.
- ^ Heldin CH. Structural and functional studies on platelet-derived growth factor. EMBO J. 1992, 11 (12): 4251–4259. PMC 556997
. PMID 1425569.
- ^ The Basic Biology of Platelet Growth Factors. [2014-05-08]. （原始内容存档于2018-10-02）.
- ^ Kumar, Vinay. Robbins and Coltran Pathologic Basis of Disease. China: Elsevier. 2010: 88–89. ISBN 978-1-4160-3121-5.
- ^ Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J, Aaronson S. Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science. 1989, 243 (4892): 800–4. PMID 2536956. doi:10.1126/science.2536956.
- ^ Heidaran MA, Pierce JH, Yu JC, Lombardi D, Artrip JE, Fleming TP, Thomason A, Aaronson SA. Role of alpha beta receptor heterodimer formation in beta platelet-derived growth factor (PDGF) receptor activation by PDGF-AB. J. Biol. Chem. 25 October 1991, 266 (30): 20232–7 [2015-05-24]. PMID 1657917. （原始内容存档于2008-11-05）.
- ^ Heidaran MA, Pierce JH, Jensen RA, Matsui T, Aaronson SA. 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. J. Biol. Chem. 5 November 1990, 265 (31): 18741–4 [2015-05-24]. PMID 2172231. （原始内容存档于2008-07-25）.
- ^ Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH. 12/15-Lipoxygenase Contributes to Platelet-derived Growth Factor-induced Activation of Signal Transducer and Activator of Transcription 3. J. Biol. Chem. December 2013, 288 (49): 35592–603. PMC 3853304 . PMID 24165129. doi:10.1074/jbc.M113.489013.
- ^ Yu JC, Li W, Wang LM, Uren A, Pierce JH, Heidaran MA. 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. J. Biol. Chem. 1995, 270 (13): 7033–6. PMID 7706238. doi:10.1074/jbc.270.13.7033.
- ^ Hoch RV, Soriano P. Roles of PDGF in animal development. Development. 2003, 130 (20): 4769–4784. PMID 12952899. doi:10.1242/dev.00721.
- ^ Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 1996, 93 (6): 2567–2581. PMC 39839 . PMID 8637916. doi:10.1073/pnas.93.6.2576.
- ^ Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996, 15 (2): 290–298. PMC 449944 . PMID 8617204.
- ^ Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993, 8 (4): 925–931. PMID 7681160.
- ^ PDGF Pathways. [2007-11-17]. （原始内容存档于2006-11-13）.
- ^ 15.0 15.1 Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin. Proc. September 2006, 81 (9): 1241–57. PMID 16970222. doi:10.4065/81.9.1241.
- ^ Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 2005, 9 (1): 59–71. PMID 15784165. doi:10.1111/j.1582-4934.2005.tb00337.x.
- ^ Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A. Role of platelet-derived growth factor in wound healing. J. Cell. Biochem. April 1991, 45 (4): 319–26. PMID 2045423. doi:10.1002/jcb.240450403.
- ^ 18.0 18.1 18.2 Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M. Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science. June 2005, 308 (5727): 1472–7. PMID 15933201. doi:10.1126/science.1107627.
- ^ Hayashi, A. The New Standard of Care for Nonunions?. AAOS Now. 2009.
- ^ Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC. Cell Death and Control of Cell Survival in the Oligodendrocyte Lineage. Cell. 1992, 70 (1): 31–46. PMID 1623522. doi:10.1016/0092-8674(92)90531-G.
- ^ 21.0 21.1 醫學主題詞表（MeSH）：Proto-Oncogene+Proteins+c-sis
- ^ McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA. FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron. November 1990, 5 (5): 603–14. PMID 2171589. doi:10.1016/0896-6273(90)90215-2.
- ^ Paul D, Lipton A, Klinger I. Serum factor requirements of normal and simian virus 40-transformed 3T3 mouse fibroplasts. Proc Natl Acad Sci U S A. 1971, 68 (3): 645–52. PMC 389008 . PMID 5276775. doi:10.1073/pnas.68.3.645.
- ^ Friedlaender GE et al. The Role of Recombinant Human Platelet-derived Growth Factor-BB (rhPDGF-BB) in Orthopaedic Bone Repair and Regeneration Curr Pharm Des. 2013;19(19):3384-90. PMID 23432673. Quote: "Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule"
- ^ Shulman T, Sauer FG, Jackman RM, Chang CN, Landolfi NF. An antibody reactive with domain 4 of the platelet-derived growth factor beta receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization. J. Biol. Chem. July 1997, 272 (28): 17400–4. PMID 9211881. doi:10.1074/jbc.272.28.17400.
- ^ McClintock JT, Chan IJ, Thaker SR, Katial A, Taub FE, Aotaki-Keen AE, Hjelmeland LM. Detection of c-sis proto-oncogene transcripts by direct enzyme-labeled cDNA probes and in situ hybridization. In Vitro Cell Dev Biol. 1992, 28A (2): 102–8. PMID 1537750. doi:10.1007/BF02631013.
- ^ Researchers make older beta cells act young again. Eurekalert.org. 2011-10-12 [2013-12-28]. （原始内容存档于2018-12-12）.
- ^ New Stanford molecular target for diabetes treatment discovered - Office of Communications & Public Affairs - Stanford University School of Medicine. Med.stanford.edu. 2011-10-12 [2013-12-28]. （原始内容存档于2013-10-21）.
- ^ Bio patch can regrow bone for dental implants and craniofacial defects. KurzweilAI. 2013-11-12 [2013-12-28]. doi:10.1016/j.biomaterials.2013.10.021. （原始内容存档于2021-01-26）.
- ^ Elangovan S, D'Mello SR, Hong L, Ross RD, Allamargot C, Dawson DV, Stanford CM, Johnson GK, Sumner DR, Salem AK. The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor. Biomaterials. 2014, 35 (2): 737–747. PMC 3855224 . PMID 24161167. doi:10.1016/j.biomaterials.2013.10.021.
