The role of Rak in the regulation of stability and function of BRCA1

BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak.

• Publication year

  2015

• Venue

  OncoTarget

• Publication date

  2015-10-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.18632/oncotarget.5717PMID 29156836PMCID 5689726
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• FRK Inhibits Migration and Invasion of Human Glioma Cells by Promoting N-cadherin/β-catenin Complex Formation

  2014cited by this paper
• miR-342 Regulates BRCA1 Expression through Modulation of ID4 in Breast Cancer

  2014cited by this paper
• HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway.

  2014cited by this paper
• FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation

  2014cited by this paper
• TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition

  2014cited by this paper
• HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway.

  2014cited by this paper
• The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor

  2014cited by this paper
• Differential effects of poly(ADP-ribose) polymerase inhibition on DNA break repair in human cells are revealed with Epstein–Barr virus

  2012cited by this paper
• Identification of BRCA1/2 Founder Mutations in Southern Chinese Breast Cancer Patients Using Gene Sequencing and High Resolution DNA Melting Analysis

  2012cited by this paper
• FRK controls migration and invasion of human glioma cells by regulating JNK/c-Jun signaling

  2012cited by this paper
• Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1.

  2012cited by this paper
• The effect of the histone deacetylase inhibitor M344 on BRCA1 expression in breast and ovarian cancer cells

  2011cited by this paper
• Mutation analysis of the FRK gene in non-small cell lung cancers.

  2011cited by this paper
• Factors determining DNA double‐strand break repair pathway choice in G2 phase

  2011cited by this paper
• Mutation analysis of the TNFAIP3 (A20) tumor suppressor gene in CLL

  2011cited by this paper
• c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells

  2011cited by this paper
• Clinical Considerations of BRCA1- and BRCA2-Mutation Carriers: A Review

  2011cited by this paper
• BRCA1 Loss Preexisting in Small Subpopulations of Prostate Cancer Is Associated with Advanced Disease and Metastatic Spread to Lymph Nodes and Peripheral Blood

  2010cited by this paper
• Mitotic DNA damage response: Polo-like Kinase-1 is dephosphorylated through ATM-Chk1 pathway

  2010cited by this paper
• HERC2 is an E3 ligase that targets BRCA1 for degradation.

  2010cited by this paper
• Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer

  2010cited by this paper
• HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.

  2010cited by this paper
• BRIT1/MCPH1 Links Chromatin Remodeling to DNA Damage Response

  2009cited by this paper
• Rak functions as a tumor suppressor by regulating PTEN protein stability and function.

  2009cited by this paper
• PALB2 Regulates Recombinational Repair through Chromatin Association and Oligomerization*

  2009cited by this paper
• Ubiquitination and downregulation of BRCA1 by ubiquitin-conjugating enzyme E2T overexpression in human breast cancer cells.

  2009influential reference
• Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

  2009cited by this paper
• Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway.

  2008cited by this paper
• Decreased BRCA1 Confers Tamoxifen Resistance in Breast Cancer Cells by Altering Estrogen Receptor-Coregulator Interactions

  2008cited by this paper
• A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair.

  2008cited by this paper
• Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.

  2008cited by this paper
• Human CtIP promotes DNA end resection

  2007cited by this paper
• Essential role for nuclear PTEN in maintaining chromosomal integrity.

  2007cited by this paper
• Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation.

  2006cited by this paper
• UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.

  2006cited by this paper
• BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy.

  2005cited by this paper
• Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair.

  2005cited by this paper
• BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.

  2005cited by this paper
• Lack of PTEN sequesters CHK1 and initiates genetic instability.

  2005cited by this paper
• Expression of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells

  2004cited by this paper
• ATR Affecting Cell Radiosensitivity Is Dependent on Homologous Recombination Repair but Independent of Nonhomologous End Joining

  2004cited by this paper
• Ubiquitination and Proteasomal Degradation of the BRCA1 Tumor Suppressor Is Regulated during Cell Cycle Progression*

  2004cited by this paper
• Hallmarks of 'BRCAness' in sporadic cancers

  2004cited by this paper
• DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains

  2004cited by this paper
• RTPrimerDB: the Real-Time PCR primer and probe database

  2003cited by this paper
• Breast and ovarian cancer.

  2003cited by this paper
• Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

  2003influential reference
• BRCA1 Directs a Selective p53-Dependent Transcriptional Response towards Growth Arrest and DNA Repair Targets

  2002cited by this paper
• Sensing and repairing DNA double-strand breaks.

  2002cited by this paper
• Characterization of Mice Deficient in the Src Family Nonreceptor Tyrosine Kinase Frk/rak

  2002cited by this paper
• BRCA1 transcriptionally regulates genes involved in breast tumorigenesis

  2002cited by this paper
• BARD1 Induces BRCA1 Intranuclear Foci Formation by Increasing RING-dependent BRCA1 Nuclear Import and Inhibiting BRCA1 Nuclear Export*

  2002cited by this paper
• Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity

  2001cited by this paper
• Involvement of Brca1 in S-Phase and G2-Phase Checkpoints after Ionizing Irradiation

  2001cited by this paper
• Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells.

  2001cited by this paper
• Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

  2001cited by this paper
• Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering.

  2000cited by this paper
• Hormone‐dependent nuclear localization of the tyrosine kinase iyk in the normal human breast epithelium and loss of expression during carcinogenesis

  2000cited by this paper
• BRCA1 Facilitates Stress-induced Apoptosis in Breast and Ovarian Cancer Cell Lines*

  2000cited by this paper
• Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1.

  1999cited by this paper
• XRCC3 promotes homology-directed repair of DNA damage in mammalian cells.

  1999cited by this paper
• BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a Brca1 transgene

  1999cited by this paper
• Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.

  1999cited by this paper
• Reduction of BRCA1 protein expression in Japanese sporadic breast carcinomas and its frequent loss in BRCA1-associated cases.

  1999cited by this paper
• Quantification of BRCA1 protein in sporadic breast carcinoma with or without loss of heterozygosity of the BRCA1 gene

  1999cited by this paper
• Double-strand break repair by interchromosomal recombination: suppression of chromosomal translocations.

  1998cited by this paper
• Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype.

  1998cited by this paper
• BRCA1 is a cell cycle-regulated nuclear phosphoprotein.

  1997cited by this paper
• Localization of BRCA1 and a splice variant identifies the nuclear localization signal

  1997cited by this paper
• Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas.

  1996cited by this paper
• iyk, a novel intracellular protein tyrosine kinase differentially expressed in the mouse mammary gland and intestine.

  1995cited by this paper
• The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb.

  1995cited by this paper
• Rak, a novel nuclear tyrosine kinase expressed in epithelial cells.

  1994cited by this paper

• Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization.

  2024cites this paper
• Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer

  2023cites this paper
• The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies

  2023cites this paper
• FRK inhibits glioblastoma progression via phosphorylating YAP and inducing its ubiquitylation and degradation by Siah1

  2022cites this paper
• BRCA1 degradation in response to mitochondrial damage in breast cancer cells

  2021cites this paper
• Nuclear Functions of the Tyrosine Kinase Src

  2020cites this paper
• BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

  2019cites this paper
• Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth

  2019cites this paper
• Haplotype-resolved and integrated genome analysis of ENCODE cell line HepG2

  2018cites this paper
• Repression of Fyn-related kinase in breast cancer cells is associated with promoter site-specific CpG methylation

  2017cites this paper
• FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition

  2017cites this paper
• Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

  2016cites this paper