Ligand-induced interaction between .alpha.- and .beta.-type platelet-derived growth factor (PDGF) receptors: role of receptor heterodimers in kinase activation

Abstract

Two types of PDGF receptors have been cloned and sequenced. Both receptors are transmembrane glycoproteins with a ligand-stimulatable tyrosine kinase site. We have shown earlier that ligand-induced activation of the beta-type PDGF receptor is due to the conversion of the monomeric form of the receptor to the dimeric form [Bishayee et al. (1989) J. Biol. Chem. 264, 11699-11705]. In the present studies, we have established the ligand-binding specificity of two receptor types and extended it further to investigate the ligand-induced association state of the alpha-receptor and the role of alpha-receptor in the activation of beta-receptor. These studies were conducted with cells that express one or the other type of PDGF receptor as well as with cells that express both types of receptors. Moreover, ligand-binding characteristics of the receptor were confirmed by immunoprecipitation of the receptor-125I-PDGF covalent complex with type-specific anti-PDGF receptor antibodies. These studies revealed that all three isoforms of PDGF bind to alpha-receptor, and such binding leads to dimerization as well as activation of the receptor. In contrast, beta-receptor can be activated only by PDGF BB and not by PDGF AB or PDGF AA. However, by using antipeptide antibodies that are specific for alpha- or beta-type PDGF receptor, we demonstrated that in the presence of alpha-receptor, beta-receptor kinase can be activated by PDGF AB. We present here direct evidence that strongly suggests that such PDGF AB induced activation of beta-receptor is due to the formation of a noncovalently linked alpha-beta receptor heterodimer.

Characterization of a Novel Epidermal‐Growth‐Factor‐Receptor‐Related 200‐kDa Tyrosine Kinase in Tumor Cells

“…2) and AbPa2 (not shown), and such recognition was abolished by cognate peptides, confirming our earlier finding that A172 expresses only the P-type PDGF receptor [8]. In A1235, an 180-kDa protein was immunoprecipitated only by AbPal and not by AbP2, indicating that A1235 expresses only the a receptor and not the preceptor.…”

“…In these studies, the 3ZP-labeled gp200 from both A172 and A1235 was purified using anti-phosphotyrosine IgG, then subjected to immunoprecipitation with a-receptor-specific and P-receptor-specific anti-peptide IgGs (Table 1). We have demonstrated earlier that AbPl and AbP2 recognize only the p-type receptor, whereas AbPal and AbPa2 are specific for the a-type receptor [8,161. AbP3, which is directed to a kinase insert domain of the P-type receptor, recognizes both the a-type and P-type receptors (Bishayee, S., unpublished results).…”

“…In this assay, detergent extracts of isolated cell membranes were phosphorylated with [y-3zP]ATP, either in the absence or presence of PDGF BB ; PDGF BB is known to stimulate the autokinase activity of both types of PDGF receptor [8]. The tyrosinephosphorylated proteins were isolated by solid-phase anti-phosphotyrosine IgG, then analyzed by SDSPAGE and autoradiography.…”

PDGF-A, PDGF-Rβ, TGFβ3 and bone morphogenic protein-4 in desmoplastic small round cell tumors with EWS-WT1 gene fusion product and their role in stromal desmoplasia: an immunohistochemical study

“…Because PDGF-Rb normally binds PDGF-BB as well as AB chains, coexpression of PDGF-A and PDGF-Rb might have an autocrine effect in desmoplastic small round cell tumors. [23][24][25] …”

Cross-talk between the proto-oncogenes Met and Ron

“…Several ligand receptors, including Platelet Derived Growth Factor, Epidermal Growth Factor and Stem Cell Factor, induce stable receptor dimerization by simultaneously binding two monomers. Ligand-bindings induce conformational changes in the receptors which promote receptor-receptor interactions (Westermark and Heldin, 1989;Kanakaraj et al, 1991;Lemmon and Schlessinger, 1994;Blechman and Yarden, 1995). Dimerization is followed by activation of the tyrosine kinase receptor by intermolecular phosphorylation events.…”