Overall structure
This gene encodes a typical receptor tyrosine kinase, which is a transmembrane protein consisting of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. The molecular mass of the mature, glycosylated PDGFRα protein is approximately 170 kDA. cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family.
Contents
- Overall structure
- Modes of activation
- Role in physiologypathology
- Interactions
- Monoclonal Antibody
- References
Modes of activation
Activation of PDGFRα requires de-repression of the receptor's kinase activity. The ligand for PDGFRα (PDGF) accomplishes this in the course of assembling a PDGFRα dimer. Four of the five PDGF isoforms activate PDGFRα (PDGF-A, PDGF-B, PDGF-AB and PDGF-C). The activated receptor phosphorylates itself and other proteins, and thereby engages intracellular signaling pathways that trigger cellular responses such as migration and proliferation. There are also PDGF-independent modes of de-repressing the PDGFRα's kinase activity and hence activating it. For instance, forcing PDGFRα into close proximity of each other by overexpression or with antibodies directed against the extracellular domain. Alternatively, mutations in the kinase domain that stabilize a kinase active conformation result in constitutive activation. Finally, growth factors outside of the PDGFR family (non-PDGFs) activate PDGFRα indirectly [1]. Non-PDGFs bind to their own receptors that trigger intracellular events that de-repress the kinase activity of PDGFRα monomers. The intracellular events by which non-PDGFs indirectly activate PDGFRα include elevation of reactive oxygen species that activate Src family kinases, which phosphorylate PDGFRα. The mode of activation determines the duration that PDGFRα remains active. The PDGF-mediated mode, which dimerized PDGFRα, accelerates internalization and degradation of activated PDGFRα such that the half-life of PDGF-activated PDGFRα is approximately 5 min [2, 3]. Enduring activation of PDGFRα (half-life greater than 120 min) occurs when PDGFRα monomers are activated [4].
Role in physiology/pathology
Adult mice with a constitutively activated PDGFRα mutant in place of one of the pdgfra alleles eventually develop fibrosis in the skin and multiple internal organs [5]. These mice do not develop gastrointestinal stromal tumor (GIST), even though the mutation that was introduced to de-repress the receptor's kinase activity was the same one found in some patients that develop this type of tumor [6]. The importance of PDGFRA during development is apparent from the observation that the majority of mice lacking pdgfra develop a plethora of embryonic defects, some of which are lethal [7]. PDGF-A and PDGF-C seem to be the important activators of PDGFRα during development because mice lacking both of pdgfa and pdgfc show similar defects to the pdgra null mice [8]. A subset of patients with GIST has mutations in PDGFRα that activate its kinase activity [6]. Such patients benefit from inhibitors that block the kinase activity of several tyrosine kinases, including PDGFRs [9]. Thus mutations that result in constitutive activation of PDGFRα are implicated in the development of tumors in patients. An intra-chromosomal fusion the PDGFR and FIP1L1 genes leads the pathological expression of the continuously active FIP1L1-PDGFRA fusion protein which is the underlying cause for the development of hypereosinophilia and a significant portion of Eosinophilic leukemias. Abe Additional ways of activating PDGFRα (overexpression or co-expression with PDGFs) are associated other types of tumors including glioblastoma and sarcomas [10, 11]. PDGF-dependent activation of PDGFRα promotes pathology in the context of stroke [12]. Stroke increases the level of proteases that generate active PDGF-C, which activates PDGFRα on perivascular cells. This relaxes the blood brain barrier and the resulting influx of plasma into the brain contributes to neurodegeneration. When activated by the indirect mode, PDGFRα promote survival during stressful conditions [13, 14]. This is because indirect activation enduringly engages PDGFRα and thereby reduces the level of p53 and thereby circumvents a checkpoint that instructs cells to perish in response to stress [15]. The consequence of surviving a stressful situation can either promote physiology or pathology, depending on the context.
Interactions
PDGFRA has been shown to interact with:
Monoclonal Antibody
Lilly has developed Olaratumab, (LY3012207) a human IgG1 monoclonal antibody designed to bind to human PDGFRα with high affinity and block PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to the receptor and is conducting clinical trials (2016) in patients with soft-tissue sarcoma.