Platelet-derived growth factor receptor
This article needs additional citations for verification. (November 2019) |
Platelet-derived growth factor receptor | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | PDGFR | ||||||||
Pfam | PF04692 | ||||||||
InterPro | IPR006782 | ||||||||
Membranome | 1204 | ||||||||
|
platelet-derived growth factor receptor, alpha polypeptide | |||||||
---|---|---|---|---|---|---|---|
Identifiers | |||||||
Symbol | PDGFRA | ||||||
NCBI gene | 5156 | ||||||
HGNC | 8803 | ||||||
OMIM | 173490 | ||||||
RefSeq | NM_006206 | ||||||
UniProt | P16234 | ||||||
Other data | |||||||
Locus | Chr. 4 q12 | ||||||
|
platelet-derived growth factor receptor, beta polypeptide | |||||||
---|---|---|---|---|---|---|---|
Identifiers | |||||||
Symbol | PDGFRB | ||||||
Alt. symbols | PDGFR | ||||||
NCBI gene | 5159 | ||||||
HGNC | 8804 | ||||||
OMIM | 173410 | ||||||
RefSeq | NM_002609 | ||||||
UniProt | P09619 | ||||||
Other data | |||||||
Locus | Chr. 5 q31-q32 | ||||||
|
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-
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 PDGF
Examination of the different signaling cascades induced by RTKs established Ras/mitogen-activated protein kinase (MAPK), PI-3 kinase, and phospholipase-
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 instead 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 serine 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. PLC
See also
[edit]- Receptor tyrosine kinase
- PDGF
- Imatinib
- PDGFRA
- PDGFRB
- Crenolanib (CP-868,596-26)
References
[edit]- ^ PDB: 3MJG; Shim AH, Liu H, Focia PJ, Chen X, Lin PC, He X (June 2010). "Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex". Proceedings of the National Academy of Sciences of the United States of America. 107 (25): 11307–12. Bibcode:2010PNAS..10711307H. doi:10.1073/pnas.1000806107. PMC 2895058. PMID 20534510.; rendered using PyMOL.
- ^ Williams LT (March 1989). "Signal transduction by the platelet-derived growth factor receptor". Science. 243 (4898): 1564–70. Bibcode:1989Sci...243.1564W. doi:10.1126/science.2538922. PMID 2538922.
- ^ Heldin CH, Westermark B (April 1989). "Platelet-derived growth factor: three isoforms and two receptor types". Trends in Genetics. 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 International. 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". Journal of Molecular Medicine. 86 (7): 785–9. doi:10.1007/s00109-008-0337-z. PMID 18392794. S2CID 21872247.
- ^ 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. S2CID 25586248.
- ^ 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. S2CID 36305139.
- ^ 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". The Journal of Biological Chemistry. 272 (51): 32670–8. 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 (December 2013). "12/15-lipoxygenase contributes to platelet-derived growth factor-induced activation of signal transducer and activator of transcription 3". The Journal of Biological Chemistry. 288 (49): 35592–603. doi:10.1074/jbc.M113.489013. PMC 3853304. 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 U.S. National Library of Medicine Medical Subject Headings (MeSH)