Unknown,Transcriptomics,Genomics,Proteomics

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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 ShcA mutant (R175Q) vs NT/ShcA cells

ORGANISM(S): Mus musculus

SUBMITTER: Sean Cory 

PROVIDER: E-GEOD-41718 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The ShcA PTB domain functions as a biological sensor of phosphotyrosine signaling during breast cancer progression.

Ahn Ryuhjin R   Sabourin Valerie V   Ha Jacqueline R JR   Cory Sean S   Maric Gordana G   Im Young Kyuen YK   Hardy W Rod WR   Zhao Hong H   Park Morag M   Hallett Michael M   Siegel Peter M PM   Pawson Tony T   Ursini-Siegel Josie J  

Cancer research 20130521 14


ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in th  ...[more]

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