CCAAT/enhancer-binding protein β: its role in breast cancer and associations with receptor tyrosine kinases

AbstractThe CCAAT/enhancer-binding proteins (C/EBPs) are a family of leucine-zipper transcription factors that regulate gene expression to control cellular proliferation, differentiation, inflammation and metabolism. Encoded by an intronless gene, C/EBPβ is expressed as several distinct protein isoforms (LAP1, LAP2, LIP) whose expression is regulated by the differential use of several in-frame translation start sites. LAP1 and LAP2 are transcriptional activators and are associated with differentiation, whereas LIP is frequently elevated in proliferative tissue and acts as a dominant-negative inhibitor of transcription. However, emerging evidence suggests that LIP can serve as a transcriptional activator in some cellular contexts, and that LAP1 and LAP2 might also have unique actions. The LIP:LAP ratio is crucial for the maintenance of normal growth and development, and increases in this ratio lead to aggressive forms of breast cancer. This review discusses the regulation of C/EBPβ activity by post-translational modification, the individual actions of LAP1, LAP2 and LIP, and the functions and downstream targets that are unique to each isoform. The role of the C/EBPβ isoforms in breast cancer is discussed and emphasis is placed on their interactions with receptor tyrosine kinases.

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Abstract S6-10: Identification of a Novel Tumor Suppressor Network Reveals a Role for Proto-Oncogenic Receptor Tyrosine Kinases in Triple-Negative Breast Cancer

10.1158/0008-5472.sabcs10-s6-10 ◽

2010 ◽

Author(s):

T Sun ◽

KL Meerbrey ◽

J Kessler ◽

M Botero ◽

I Migliaccio ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Triple Negative Breast Cancer ◽

Tyrosine Kinases ◽

Triple Negative ◽

Receptor Tyrosine Kinases

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Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer

The Journal of Pathology ◽

10.1002/path.1370 ◽

2003 ◽

Vol 200 (3) ◽

pp. 290-297 ◽

Cited By ~ 382

Author(s):

Caroline J Witton ◽

Jonathan R Reeves ◽

James J Going ◽

Timothy G Cooke ◽

John MS Bartlett

Keyword(s):

Breast Cancer ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases

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Src Family Kinases Are Required for Prolactin Induction of Cell Proliferation

Molecular Biology of the Cell ◽

10.1091/mbc.12.7.2171 ◽

2001 ◽

Vol 12 (7) ◽

pp. 2171-2183 ◽

Cited By ~ 50

Author(s):

Juan Ángel Fresno Vara ◽

Ma Aurora Domı́nguez Cáceres ◽

Augusto Silva ◽

Jorge Martı́n-Pérez

Keyword(s):

Cell Proliferation ◽

Tyrosine Kinases ◽

Cellular Proliferation ◽

Tyrosine Phosphatase ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Herbimycin A ◽

Serine Kinases ◽

Dependent Cell

Prolactin (PRL) is a pleiotropic cytokine promoting cellular proliferation and differentiation. Because PRL activates the Src family of tyrosine kinases (SFK), we have studied the role of these kinases in PRL cell proliferation signaling. PRL induced [3H]thymidine incorporation upon transient transfection of BaF-3 cells with the PRL receptor. This effect was inhibited by cotransfection with the dominant negative mutant of c-Src (K>A295/Y>F527, SrcDM). The role of SFK in PRL-induced proliferation was confirmed in the BaF-3 PRL receptor-stable transfectant, W53 cells, where PRL induced Fyn and Lyn activation. The SFK-selective inhibitors PP1/PP2 and herbimycin A blocked PRL-dependent cell proliferation by arresting the W53 cells in G1, with no evident apoptosis. In parallel, PP1/PP2 inhibited PRL induction of cell growth-related genes c-fos, c-jun, c-myc, andodc. These inhibitors have no effect on PRL-mediated activation of Ras/Mapk and Jak/Start pathways. In contrast, they inhibited the PRL-dependent stimulation of the SFKs substrate Sam68, the phosphorylation of the tyrosine phosphatase Shp2, and the PI3K-dependent Akt and p70S6k serine kinases. Consistently, transient expression of SrcDM in W53 cells also blocked PRL activation of Akt. These results demonstrate that activation of SFKs is required for cell proliferation induced by PRL.

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Editorial: Targeting Neuregulin1 and HER Receptor Tyrosine Kinases for Therapy of Breast Cancer and Heart Failure

Current Pharmaceutical Design ◽

10.2174/1381612819666131125161550 ◽

2014 ◽

Vol 20 (30) ◽

pp. 4854-4855

Author(s):

Xinhua Yan

Keyword(s):

Breast Cancer ◽

Heart Failure ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases

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The Three Receptor Tyrosine Kinases c-KIT, VEGFR2 and PDGFRα, Closely Spaced at 4q12, Show Increased Protein Expression in Triple-Negative Breast Cancer

PLoS ONE ◽

10.1371/journal.pone.0102176 ◽

2014 ◽

Vol 9 (7) ◽

pp. e102176 ◽

Cited By ~ 19

Author(s):

Sara Jansson ◽

Pär-Ola Bendahl ◽

Dorthe Aamand Grabau ◽

Anna-Karin Falck ◽

Mårten Fernö ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Triple Negative Breast Cancer ◽

Tyrosine Kinases ◽

Triple Negative ◽

Receptor Tyrosine Kinases

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Evolution of functional diversity in the holozoan tyrosine kinome

10.1101/2021.08.03.454916 ◽

2021 ◽

Author(s):

Wayland Yeung ◽

Annie Kwon ◽

Rahil Taujale ◽

Claire Bunn ◽

Aarya Venkat ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Cell Communication ◽

Kinase Domain ◽

Model Organisms ◽

Post Translational Modification ◽

Functional Features ◽

Conformational Regulation ◽

Insulin Receptor Kinase

The emergence of multicellularity is strongly correlated with the expansion of tyrosine kinases, a conserved family of signaling enzymes that regulates pathways essential for cell-to-cell communication. Although tyrosine kinases have been classified from several model organisms, a molecular-level understanding of tyrosine kinase evolution across all holozoans is currently lacking. Using a hierarchical sequence constraint-based classification of diverse holozoan tyrosine kinases, we construct a new phylogenetic tree that identifies two ancient clades of cytoplasmic and receptor tyrosine kinases separated by the presence of an extended insert segment in the kinase domain connecting the D and E-helices. Present in nearly all receptor tyrosine kinases, this fast-evolving insertion imparts diverse functionalities such as post-translational modification sites and regulatory interactions. The two exceptions which lack this insert, Eph and EGFR receptor tyrosine kinases, each form an independent lineage characterized by unique functional features. We also identify common constraints shared across multiple tyrosine kinase families which warrant the designation of three new subgroups: Src module (SrcM), insulin receptor kinase-like (IRKL), and Fibroblast, Vascular, and Platelet-derived growth factor Receptors (FPVR). Subgroup-specific constraints reflect shared autoinhibitory interactions involved in kinase conformational regulation. Conservation analyses describe how diverse tyrosine kinase signaling functions arose through the addition of family-specific motifs upon subgroup-specific features and co-conserved protein domains. We propose the oldest tyrosine kinases, IRKL, SrcM and Csk, originated from unicellular pre-metazoans and were co-opted for complex multicellular functions. The increased frequency of oncogenic variants in more recent tyrosine kinases suggests that lineage-specific functionalities are selectively altered in human cancers.

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Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling

The Journal of Cell Biology ◽

10.1083/jcb.201902073 ◽

2021 ◽

Vol 220 (2) ◽

Author(s):

Ana Lonic ◽

Freya Gehling ◽

Leila Belle ◽

Xiaochun Li ◽

Nicole L. Schieber ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Tyrosine Kinases ◽

Breast Cancer Cells ◽

Triple Negative ◽

Receptor Tyrosine Kinases ◽

Breast Cancer Patients ◽

Egfr Signaling ◽

Late Endosomes ◽

Endosome Maturation

Receptor degradation terminates signaling by activated receptor tyrosine kinases. Degradation of EGFR occurs in lysosomes and requires the switching of RAB5 for RAB7 on late endosomes to enable their fusion with the lysosome, but what controls this critical switching is poorly understood. We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. The rapid association of phospho-Y374-PKCδ with EGFR-containing endosomes is diminished by PTPN14, which dephosphorylates phospho-Y374-PKCδ. In triple-negative breast cancer cells, the FER-dependent phosphorylation of PKCδ enhances EGFR signaling and promotes anchorage-independent cell growth. Importantly, increased Y374-PKCδ phosphorylation correlating with arrested late endosome maturation was identified in ∼25% of triple-negative breast cancer patients, suggesting that dysregulation of this pathway may contribute to their pathology.

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