Oncogenic activation of the αPDGFR defines a domain that negatively regulates receptor dimerization

Uren, Akyut; Yu, Jin Chen; Karçaaltıncaba, Muşturay; Pierce, Jacalyn H.; Heidaran, Mohammad A.

doi:10.1038/sj.onc.1200810

Cited by 17 publications

(9 citation statements)

References 13 publications

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“…The second Ig-like domain appears to be more critical in preventing spontaneous receptor dimerization, and this correlates with the more important role played by this domain in NGF binding (24,33,34,36). In platelet-derived growth factor receptors, Ig-like domains 1 to 3 participate in ligand binding; however, only deletion of the Ig-like domain 3 caused oncogenic activation (32). Chimeric receptors between TrkA and c-Kit demonstrated that dimerization could also be achieved by retaining the Iglike structure but exchanging the TrkA Ig-like domains for a c-Kit domain responsible for dimerization.…”

Section: Discussionmentioning

confidence: 99%

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Arévalo

Conde

Hempstead

et al. 2000

Molecular and Cellular Biology

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The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.

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Section: Discussionmentioning

confidence: 99%

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Arévalo

Conde

Hempstead

et al. 2000

Molecular and Cellular Biology

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“…A mutant PDGFA receptor lacking Ig-like domain 3 results in growth factor-independent receptor dimerization and activation (55), and an Ig-like domain contained within the extracellular domain of the TrkA receptor serves a similar function (56). Interestingly, the structural features of the PDGF receptor A and TrkA receptors that participate in these effects are contained within the receptor's ligand binding domains.…”

Section: Discussionmentioning

confidence: 99%

Kinase Insert Domain Receptor (KDR) Extracellular Immunoglobulin-like Domains 4–7 Contain Structural Features That Block Receptor Dimerization and Vascular Endothelial Growth Factor-induced Signaling

Tao

Backer

et al. 2001

Journal of Biological Chemistry

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The vascular endothelial growth factor (VEGF) receptor tyrosine kinase subtype kinase insert domain receptor (KDR) contains seven extracellular Ig-like domains, of which the three most amino-terminal contain the necessary structural features required for VEGF binding. To clarify the functional role of KDR Ig-like domains 4-7, we compared VEGF-induced signaling in human embryonic kidney and porcine aortic endothelial cells expressing native versus mutant receptor proteins in which Ig-like domains 4-7, 4-6, or 7 had been deleted. Western blotting using an anti-receptor antibody indicated equivalent expression levels for each of the recombinant proteins. As expected, VEGF treatment robustly augmented native receptor autophosphorylation. In contrast, receptor autophosphorylation, as well as downstream signaling events, were VEGF-independent for cells expressing mutant receptors. 125I-VEGF 165 bound with equal or better affinity to mutant versus native receptor, although the number of radioligand binding sites was significantly reduced because a significant percentage of mutant, but not native, receptors were localized to the cell interior. As was the case for native KDR, 125

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“…7D) unequivocally demonstrates that the efficient homodimerization of the truncated RPTP␣ can occur in a ligand-independent fashion. However, since some truncated receptor PTKs lacking all or part of the ECD undergo ligand-independent dimerization, whereas the full-length receptors do not (15,22,57), the fact that the RPTP␣ ECD deletion mutant dimerized does not necessarily imply that the dimerization of full-length RPTP␣ is also ligand independent. So far, we have been unable to cross-link endogenous RPTP␣ in embryonic fibroblasts or retrovirally transduced RPTP␣ in RPTP␣ Ϫ/Ϫ embryonic fibroblasts derived from RPTP␣ Ϫ/Ϫ mice (50).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface

Jiang

Hertog

Hunter

2000

Molecular and Cellular Biology

125

146

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We reported previously that the N-terminal D1 catalytic domain of receptor protein-tyrosine phosphatase ␣ (RPTP␣) forms a symmetrical, inhibited dimer in a crystal structure, in which a helix-turn-helix wedge element from one monomer is inserted into the catalytic cleft of the other monomer. Previous functional studies also suggested that dimerization inhibits the biological activity of a CD45 chimeric RPTP and the catalytic activity of an isolated RPTP D1 catalytic domain. Most recently, we have also shown that enforced dimerization inhibits the biological activity of full-length RPTP␣ in a wedge-dependent manner. The physiological significance of such inhibition is unknown, due to a lack of understanding of how RPTP␣ dimerization is regulated in vivo. In this study, we show that transiently expressed cell surface RPTP␣ exists predominantly as homodimers, suggesting that dimerization-mediated inhibition of RPTP␣ biological activity is likely to be physiologically relevant. Consistent with our published and unpublished crystallographic data, we show that mutations in the wedge region of D1 catalytic domain and deletion of the entire D2 catalytic domain independently reduced but did not abolish RPTP␣ homodimerization, suggesting that both domains are critically involved but that neither is essential for homodimerization. Finally, we also provide evidence that both the RPTP␣ extracellular domain and the transmembrane domain were independently able to homodimerize. These results lead us to propose a zipper model in which inactive RPTP␣ dimers are stabilized by multiple, relatively weak dimerization interfaces. Dimerization in this manner would provide a potential mechanism for negative regulation of RPTP␣. Such RPTP␣ dimers could be activated by extracellular ligands or intracellular binding proteins that induce monomerization or by intracellular signaling events that induce an open conformation of the dimer.Protein-tyrosine phosphorylation plays a vital role in many cellular processes including growth and differentiation (18,54). Cellular levels of tyrosine phosphorylation are maintained by a balance between protein-tyrosine kinase (PTK) and proteintyrosine phosphatase (PTP) activity (18). At present, more than 75 PTP family members have been identified, and it has been suggested that the human genome could encode more than a hundred PTPs (54). The PTP superfamily is subdivided into three subfamilies: the dual-specificity PTPs, the intracellular PTPs, and the receptor-like PTPs (RPTPs) (49). Most RPTPs have tandem catalytic domains, with the majority of catalytic activity residing in the membrane-proximal catalytic domain (D1). While it is well established that ligand binding to receptor PTKs results in dimerization, transautophosphorylation, and kinase activation (16), how the activity of RPTPs is regulated remains poorly understood. Only a handful of RPTPs have been found to bind to other proteins via their extracellular domains (ECDs), and until recently none of these interacting proteins had been found to modu...

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Oncogenic activation of the αPDGFR defines a domain that negatively regulates receptor dimerization

Cited by 17 publications

References 13 publications

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Kinase Insert Domain Receptor (KDR) Extracellular Immunoglobulin-like Domains 4–7 Contain Structural Features That Block Receptor Dimerization and Vascular Endothelial Growth Factor-induced Signaling

Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface

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