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The ShcA PTB Domain Functions as a Biological Sensor of Phospho-tyrosine Signaling During Breast Cancer Progression

ABSTRACT: The ShcA adaptor possesses two phosphotyrosine binding motifs, which include an SH2 and a PTB domain. In the majority of cases, ShcA utilizes its PTB domain to engage activated receptor tyrosine kinases (RTKs). To establish the mportance of this domain during mammary tumorigenesis, we employed a ShcA mutant (R175Q) that no longer binds phospho-tyrosine residues via its PTB domain. We demonstrate that the ShcR175Q mutant delays mammary tumor onset n MMTV/MT transgenic animals. Paradoxically, we observe a robust increase in the growth and angiogenesis of emerging mammary tumors. ShcR175Q-expressing breast cancer cells increase fibronectin secretion and possess elevated levels f integrin α5/β1, the principle fibronectin receptor. Sustained integrin engagement activates Src, which in turn phosphorylates pro-angiogenic RTKs, including PDGFR, FGFR and Met, leading to increased VEGF secretion from ShcR175Q-xpressing breast cancer cells. Finally, we describe a ShcR175Q-dependent gene signature that stratifies breast cancer patients with a high microvessel density. This is the first study to demonstrate that intracellular signaling pathways ownstream of the ShcA PTB domain both positively and negatively regulate tumorigenesis during the various stages of breast cancer progression

ORGANISM(S): Mus musculus

PROVIDER: GSE41718 | GEO | 2013/08/07

SECONDARY ACCESSION(S): PRJNA178013

REPOSITORIES: GEO

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The ShcA PTB Domain Functions as a Biological Sensor of Phospho-tyrosine Signaling During Breast Cancer Progression

Project description:The ShcA adaptor possesses two phosphotyrosine binding motifs, which include an SH2 and a PTB domain. In the majority of cases, ShcA utilizes its PTB domain to engage activated receptor tyrosine kinases (RTKs). To establish the mportance of this domain during mammary tumorigenesis, we employed a ShcA mutant (R175Q) that no longer binds phospho-tyrosine residues via its PTB domain. We demonstrate that the ShcR175Q mutant delays mammary tumor onset n MMTV/MT transgenic animals. Paradoxically, we observe a robust increase in the growth and angiogenesis of emerging mammary tumors. ShcR175Q-expressing breast cancer cells increase fibronectin secretion and possess elevated levels f integrin α5/β1, the principle fibronectin receptor. Sustained integrin engagement activates Src, which in turn phosphorylates pro-angiogenic RTKs, including PDGFR, FGFR and Met, leading to increased VEGF secretion from ShcR175Q-xpressing breast cancer cells. Finally, we describe a ShcR175Q-dependent gene signature that stratifies breast cancer patients with a high microvessel density. This is the first study to demonstrate that intracellular signaling pathways ownstream of the ShcA PTB domain both positively and negatively regulate tumorigenesis during the various stages of breast cancer progression ShcA mutant (R175Q) vs NT/ShcA cells

2013-08-07 | E-GEOD-41718 | biostudies-arrayexpress

Conditional loss of ErbB3 delays mammary gland hyperplasias induced by mutant PIK3CA but does not affect mammary tumor latency, gene expression or signaling

Project description:Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, induce transformation of mammary epithelial cells (MEC). Studies suggest the transforming action of mutant PIK3CA requires binding to activated receptor tyrosine kinases or adaptors. We examined in transgenic mice if ErbB3, a powerful activator of PI3K, is required for mutant PIK3CA-mediated MEC transformation. ErbB3 loss delayed PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression and markers of PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with other tyrosine phosphorylated adaptors, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Combined inhibition of ErbB RTKs and PI3K with lapatinib and the p110α inhibitor BYL719, respectively, reduced PIK3CAH1047R-dependent tumor growth and PI3K signaling more potently than the p110α inhibitor alone. In human breast cancer cells harboring PIK3CAH1047R, the combination with BYL719 and an ErbB3 inhibitor synergistically inhibited tumor growth and P-Akt. These data suggest that basal tumor growth and PI3K signaling do not depend on ErbB RTKs in PIK3CAH1047R-expressing tumors. However, upon inhibition of p110α, these receptors limit the action of PI3K inhibitors potentially explaining the more potent effect of the combination against PI3K-mutant cancers. reference x sample

2013-06-20 | E-GEOD-43037 | biostudies-arrayexpress

Mus musculus

Project description:The ShcA PTB Domain Functions as a Biological Sensor of Phospho-tyrosine Signaling During Breast Cancer Progression

| PRJNA178013 | ENA

Conditional loss of ErbB3 delays mammary gland hyperplasias induced by mutant PIK3CA but does not affect mammary tumor latency, gene expression or signaling

2013-06-20 | GSE43037 | GEO

An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation

Project description:The ErbB4 receptor isoforms JM-a and JM-b differ within their extracellular juxtamembrane (eJM) domains. Here, ErbB4 isoforms are used as a model to address the effect of structural variation in the eJM domain of receptor tyrosine kinases (RTK) on downstream signaling. A specific JM-a-like sequence motif is discovered, and its presence or absence (in JM-b-like RTKs) in the eJM domains of several RTKs is demonstrated to dictate selective STAT activation. STAT5a activation by RTKs including the JM-a like motif is shown to involve interaction with oligosaccharides of N-glycosylated cell surface proteins such as β1 integrin, whereas STAT5b activation by JM-b is dependent on TYK2. ErbB4 JM-a- and JM-b-like RTKs are shown to associate with specific signaling complexes at different cell surface compartments using analyses of RTK interactomes and super-resolution imaging. These findings provide evidence for a conserved mechanism linking a ubiquitous extracellular motif in RTKs with selective intracellular STAT signaling.

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An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation

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Spatial Transcriptomics Suggests That Alterations 4 Occur in the Preneoplastic Breast Microenvironment of 5 Q2 BRCA1/2 Mutation Carriers

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Nudt3 is a mRNA Decapping Enzyme That Modulates Cell Migration

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2016-07-21 | GSE75146 | GEO

Nudt3 is a mRNA Decapping Enzyme That Modulates Cell Migration

Project description:The Dcp2 and Nudt16 Nudix hydrolases, are mRNA decapping enzymes that preferentially modulate stability of a subset of mRNAs. Here we report Nudt3 is a third Nudix protein that possess mRNA decapping activity in cells and is a modulator of cell migration in MCF-7 breast cancer cells. Genome-wide analysis of Nudt3 compromised cells identified increases in mRNAs involved in cell motility including integrin Î²6, lipocalin-2 and fibronectin. The increase in mRNA levels was dependent on Nudt3 decapping activity where integrin Î²6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 depleted cells was mediated through the extracellular integrin Î²6 and fibronectin protein nexus. We conclude, Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals. Stably transformed MCF-7 cell lines constitutively expressing either a short hairpin RNA (shRNA) directed against Nudt3 (Nudt3KD) or a non-targeted control shRNA (ConKD) were used, with three replicate cultures used per group (n=3).

2016-07-21 | E-GEOD-75146 | biostudies-arrayexpress

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