Platelet-derived growth factor receptor

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Platelet-derived growth factor receptor
Ribbon image of two molecules of human PDGF receptor beta (yellow and magenta) in complex with dimeric PDGF-B (cyan and green).[1]
Identifiers
SymbolPDGFR
PfamPF04692
InterProIPR006782
Membranome1204
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Chr. 4 q12
Search for
StructuresSwiss-model
DomainsInterPro
Chr. 5 q31-q32
Search for
StructuresSwiss-model
DomainsInterPro

Platelet-derived growth factor receptors (PDGF-R) are cell surface

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

The PDGF family consists of PDGF-A, -B, -C and -D, which form either homo- or hetero

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

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
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

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

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

MAPK pathway

The adaptor protein Grb2 forms a complex with Sos by the Grb2

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

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

References

  1. PMID 20534510.; rendered using PyMOL
    .
  2. PMID 2538922
    .
  3. PMID 2543106
    .
  4. PMID 1315403
    .
  5. S2CID 21872247
    .
  6. S2CID 25586248
    .
  7. S2CID 36305139
    .
  8. PMID 9405485
    .
  9. PMID 24165129
    .
  10. ^ Schlessinger, J. SH2/SH3 Signaling Proteins. Curr. Op. Gen. Dev. 1994, 4(1):25-30.

External links

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