Platelet-derived growth factor receptor
Encyclopedia
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptor
s 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
. There are two forms of the PDGF-R, alpha
and beta
each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
s (PDGF-AA, -AB, -BB, -CC, -DD). The four PDGFs are inactive in their monomer
ic forms. The PDGFs bind to the protein tyrosine kinase receptor
s PDGF receptor-α and -β. These two receptor isoforms dimer
ize 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.
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 change
s, 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 substrate
s 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.
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. 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 cascade
s, induced by RTK
s, established Ras/mitogen-activated protein kinase (MAPK),PI-3 kinase and phospholipase-γ (PLCγ) pathways as key downstream mediators of the PDGFR signalling.
, 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 Syp/PTP1D protein, Grb2 binds to activated EGFR through Shc, another adaptor protein that forms a complex with many receptors via its PTB domain. (Schlessinger, J. SH2/SH3 Signaling Proteins. Curr. Op. Gen. Dev. 1994, 4: 25-30.) 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.
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s for members of the platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF) family. PDGF subunits -A
PDGFA
Platelet-derived growth factor subunit A is a protein that in humans is encoded by the PDGFA gene.-Further reading:...
and -B
PDGFB
Platelet-derived growth factor subunit B is a protein that in humans is encoded by the PDGFB gene.-Further reading:...
are important factors regulating cell proliferation, cellular differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, development
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
and many diseases including cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. There are two forms of the PDGF-R, alpha
PDGFRA
Alpha-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRA gene.-Interactions:PDGFRA has been shown to interact with PDGFRB, PLCG1, Sodium-hydrogen antiporter 3 regulator 1, Cbl gene, CRK, Caveolin 1 and PDGFC.-Further reading:...
and beta
PDGFRB
Beta-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRB gene.-Interactions:PDGFRB has been shown to interact with PTPN11, NCK1, Grb2, Caveolin 1, PDGFRA, Sodium-hydrogen antiporter 3 regulator 1, RAS p21 protein activator 1, CRK, SHC1 and...
each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
Mechanism of action
The PDGF family consists of PDGF-A, -B, -C and -D, which form either homo- or heterodimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s (PDGF-AA, -AB, -BB, -CC, -DD). The four PDGFs are inactive in their monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
ic forms. The PDGFs bind to the protein tyrosine kinase receptor
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s PDGF receptor-α and -β. These two receptor isoforms dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
ize upon binding the PDGF dimer, leading to three possible receptor combinations, namely -αα, -ββ and -αβ. The extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
region of the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
consists of five immunoglobulin-like domains while the intracellular part is a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
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.
Dimerization is a prerequisite for the activation
Activation
Activation in chemical sciences generally refers to the process whereby something is prepared or excited for a subsequent reaction.- Chemistry :...
of the kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. Kinase activation is visualized as tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the receptor molecules, which occurs between the dimerized receptor molecules (transphosphorylation). In conjunction with dimerization and kinase activation, the receptor molecules undergo conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
s, which allow a basal kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity to phosphorylate a critical tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residue, thereby "unlocking" the kinase, leading to full enzymatic
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
activity directed toward other tyrosine residues in the receptor molecules as well as other substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
s 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
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, 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
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 transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
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
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
at this position have reduced kinase activity. Tyr-857 has therefore been assigned a role in positive regulation of kinase activity. 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 cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
s, induced by RTK
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s, established Ras/mitogen-activated protein kinase (MAPK),PI-3 kinase and phospholipase-γ (PLCγ) pathways as key downstream mediators of the PDGFR signalling.
MAPK pathway
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 Syp/PTP1D (Also known as PTPN11PTPN11
Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
, a cytosolic PTP
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...
), 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 Syp/PTP1D protein, Grb2 binds to activated EGFR through Shc, another adaptor protein that forms a complex with many receptors via its PTB domain. (Schlessinger, J. SH2/SH3 Signaling Proteins. Curr. Op. Gen. Dev. 1994, 4: 25-30.) 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
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.See also
- Receptor tyrosine kinaseReceptor tyrosine kinaseReceptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
- PDGF
- ImatinibImatinibImatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
- PDGFRBPDGFRBBeta-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRB gene.-Interactions:PDGFRB has been shown to interact with PTPN11, NCK1, Grb2, Caveolin 1, PDGFRA, Sodium-hydrogen antiporter 3 regulator 1, RAS p21 protein activator 1, CRK, SHC1 and...
- Crenolanib (CP-868,596-26)
External links
- http://angiogenesis.amgen.com