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Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL [copy number]

ABSTRACT: Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention. Primary ALL samples were investigated on Affymetrix SNP 6.0 arrays for copy-number changes related to receptor tyrosine kinases (RTKs). Buffy-Coat samples of healthy persons were used as reference.

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Streichert

PROVIDER: E-GEOD-42054 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL [gene expression]

Project description:Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention. Three different primary ALL samples expressing FLT3 and/or PDGFRß were stimulated with the corresponding ligands FLT3L and PDGF-BB for five time points. Unstimulated samples served as control. ALL22089 coexpresses FLT3 and PDGFRß. ALL109 expresses PDGFRß. ALL114 expresses FLT3.

2014-11-03 | E-GEOD-42001 | biostudies-arrayexpress

Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL [gene expression]

2014-11-03 | GSE42001 | GEO

Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL [copy number]

2014-11-03 | GSE42054 | GEO

Receptor tyrosine kinase dependent phospho-signaling networks determine cellular growth and survival in acute lymphoblastic leukemia

Project description:Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor β (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3 D835H PDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.

2019-11-22 | PRD000749 | Pride

Physical and functional interactome of human receptor tyrosine kinases

Project description:Much cell-to-cell communication is facilitated by cell surface receptor tyrosine kinases (RTKs). These proteins phosphorylate their downstream cytoplasmic substrates in response to stimuli such as growth factors. Despite their central roles, the functions of many RTKs are still poorly understood. To resolve the lack of systemic knowledge, we used three complementary methods to map the molecular context and substrate profiles of RTKs. We used affinity purification coupled to mass spectrometry (AP-MS) to characterize stable binding partners and RTK-protein complexes, proximity-dependent biotin identification (BioID) to identify transient and proximal interactions, and an in vitro kinase assay to identify RTK substrates. To identify how kinase interactions depend on kinase activity, we also used kinase-deficient mutants. Our data represent a comprehensive, systemic mapping of RTK interactions and substrates. This resource adds information regarding well-studied RTKs, offers insights into the functions of less well-studied RTKs, and highlights RTK-RTK interactions and shared signaling pathways

2021-07-14 | MSV000087816 | MassIVE

PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer

Project description:Mutations or amplifications of receptor tyrosine kinases (RTKs) are common in many cancers. Given the emergence of small molecule inhibitors specific to RTKs, these signalling cascades are attractive therapeutic targets. However, compensatory and adaptation mechanisms limit the clinical utility of compounds that target nodes in RTK networks. Here we show that PHLDA1 down-regulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer.

2018-02-19 | GSE81169 | GEO

Large-scale phosphorylation site interaction proteomics

Project description:Receptor tyrosine kinases (RTKs) are membrane proteins that regulate complex, multilayered signaling networks centered on tyrosine phosphorylation of proteins with broad implications in human health and disease. Here we developed a large-scale mass spectrometry-based proteomics platform for investigation of in-vivo RTK signaling networks and the dynamic protein interactions they induce.

2019-10-04 | PXD004055 | Pride

Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL

Project description:Diverse phospho-signaling networks mediate RTK dependent growth and survival in childhood ALL

| PRJNA179033 | ENA

A Global Analysis of Receptor Tyrosine Kinase – Protein Phosphatase Interactome

Project description:Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. However, a comprehensive picture of how RTKs functionally associate with phosphatases remains elusive. We aimed to study this problem by using two protein-protein interaction (PPI) approaches, the Membrane Yeast Two-Hybrid (MYTH) and the Mammalian Membrane Two-Hybrid (MaMTH), to map the PPIs between 48 human RTKs and 126 phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of novel interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTP) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling. We further investigated the biological functions of several interactors, and found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. In contrast, PTPRA plays a dual role in EGFR signaling since besides dephosphorylating EGFR, it conversely enhances downstream ERK signaling through activating SRC. We present the first comprehensive RTK-phosphatase interactome study, providing a broad and deep view of RTK signaling.

2017-01-11 | PXD004248 | Pride

Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Project description:The HMG-box protein Capicua (Cic) is a conserved transcriptional repressor that functions downstream of receptor tyrosine kinase (RTK) signaling pathways in a relatively simple switch: in the absence of signaling, Cic represses RTK-responsive genes by binding to nearly invariant sites in DNA, whereas activation of RTK signaling downregulates Cic activity, leading to derepression of its targets. This mechanism controls gene expression in both Drosophila and mammals, but whether Cic can also function via other regulatory mechanisms remains unknown. Here we characterize an RTK-independent role of Cic in regulating spatially restricted expression of Toll/IL-1 signaling targets in Drosophila embryogenesis. We show that Cic represses those targets by binding to suboptimal DNA sites of lower affinity than its known consensus sites. This binding depends on Dorsal/NF-kB, which translocates into the nucleus upon Toll activation and binds next to the Cic sites. As a result, Cic binds to and represses Toll targets only in regions with nuclear Dorsal. These results reveal a new mode of Cic regulation unrelated to the well-established RTK-Cic depression axis and implicate cooperative binding in conjunction with low-affinity binding sites as an important mechanism of enhancer regulation. Given that Cic plays a role in many developmental and pathological processes in mammals, our results raise the possibility that some of these Cic functions are independent of RTK regulation and may depend on cofactor-assisted DNA binding.

2018-01-05 | GSE104839 | GEO

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