AATYK: A novel tyrosine kinase induced during growth arrest and apoptosis of myeloid cells

Gaozza, Eugenia; Sj, Baker; Rk, Vora; Ep, Reddy

doi:10.1038/sj.onc.1201575

Cited by 70 publications

(81 citation statements)

References 17 publications

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“…Exogenous AATK inhibits melanoma cellular proliferation in complete media without affecting apoptosis AATK: growth inhibitor and apoptosis promoter in melanoma S Ma and BP Rubin (data not shown), whereas the pro-apoptotic function of AATK is only observed in the apoptosis induced by depriving cells of growth factors and nutrients, including amino acids, glucose, and potassium chloride. This pro-apoptotic function of AATK is similar to what has been observed in myeloid precursor cells 1 and cerebellar granule cells. 9 A previous study has shown a physical interaction between AATK and Src in mouse brain microsome fractions and COS 7 cells.…”

Section: Discussionsupporting

confidence: 65%

“…1 It is predominantly expressed at high levels in different regions of the brain, whereas at relatively low levels in other tissues including heart, lung, kidney, and skeletal muscle. [1][2][3][4] AATK contains a tyrosine kinase domain at the N-terminus and a proline-rich SH3-binding motif consisting of 16 PXXP motifs at the C-terminus. Two isoforms of AATK have been reported and referred to as AATKA and AATKB.…”

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confidence: 99%

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Apoptosis-associated tyrosine kinase 1 inhibits growth and migration and promotes apoptosis in melanoma

Rubin

2014

Laboratory Investigation

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Apoptosis-associated tyrosine kinase 1 (AATK1) was initially identified as a protein that was dramatically overexpressed during growth arrest and apoptosis of 32Dcl myeloblastic leukemia cells. AATK is expressed in different regions of the brain and may have a role in normal nervous system development by its dual functions of enhancing apoptosis of mature granule cells and promoting terminal neuronal differentiation of developing neurons. However, its function in cancer has never been studied. Melanoma is a tumor composed of transformed cells within the melanocyte lineage deriving from the embryonic neural crest. It has been shown that developmental pathways in neural crest cells have a direct bearing on melanoma formation and human metastatic melanoma cells express a dedifferentiated phenotype. We found that the expression levels of AATK are lower in metastatic melanoma cell lines compared with primary melanoma cell lines and normal human melanocytes. We found that depletion of AATK mRNA in metastatic melanoma cell lines enhanced cell migration in cell line derived from metastatic melanomas. Overexpression of AATK inhibited cell proliferation, colony formation, and promoted apoptosis in melanoma cell lines derived from primary and metastatic melanomas. Signal transduction pathway analysis revealed that Src is involved in regulating AATK. Our results demonstrate for the first time that AATK inhibits cell proliferation, colony formation, and migration, and also promotes apoptosis in melanoma cells.

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Section: Discussionsupporting

confidence: 65%

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confidence: 99%

Apoptosis-associated tyrosine kinase 1 inhibits growth and migration and promotes apoptosis in melanoma

Rubin

2014

Laboratory Investigation

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“…25,26 In our laboratory, Ͼ95% of the cells are nonviable by 48 h after IL-3 withdrawal as measured by a number of independent assays; including trypan blue exclusion, annexin V or propidium iodide (PI) staining followed by fluorescence activated cell sorting (FACS) analysis. The results shown in Figure 1a, demonstrate that cells first become annexin V positive (an early marker of apoptosis) and then subsequently stain for PI (a marker of dead cells).…”

Section: Retroviral Cdna Library Screen For Anti-apoptotic Genesmentioning

confidence: 99%

Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression

et al. 2002

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The balance between hematopoietic cell viability and apoptosis is regulated by exogenous growth factors, however, the molecular mechanisms by which these trophic factors exert their effects remain obscure. A functional retroviral cDNA librarybased screen was employed to identify genes that prevent growth factor withdrawal-mediated apoptosis in the myeloid progenitor cell 32Dcl3. This approach identified three classes of genes: those with known roles in apoptosis (bcl-X L and ornithine decarboxylase); genes previously identified but not linked directly to apoptotic signaling (O-linked N-acetylglucosamine transferase); and a previously uncharacterized gene we termed SPIN-2. In 32Dcl3 cells, expression of exogenous SPIN-2 provides 25% protection from apoptosis following growth factor withdrawal compared to controls which show ෂ1-2% survival. SPIN-2 overexpression slows cell growth rates and increases the percentage of cells in G 2 /M (32% vs control cells at 12%).Immunolocalization studies indicate that myc-epitope tagged SPIN-2 proteins, which retain their anti-apoptotic function, reside in the nucleus, whereas a C-terminal deletion mutant that loses its anti-apoptotic activity is located in the cytoplasm. These studies suggest that SPIN-2 is a novel nuclear protein that functions to regulate cell cycle progression and this activity is related to the inhibition of apoptosis following the removal of essential growth factors.

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“…Finally, the downstream sequence (about 130 bp) of IRSp53 was overlapped with the AATK gene, which encoded apoptosis-associated tyrosine kinase (Gaozza et al 1997) (Fig. 4).…”

Section: Genomic Organization In Rodentsmentioning

confidence: 99%

Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein

Miyahara

Okamura-Oho²,

Miyashita³

et al. 2003

J Hum Genet

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Insulin receptor tyrosine kinase substrate of 53-kDa protein (IRSp53) is now known to be a key factor in cytoskeleton reorganization. The human IRSp53 was identified as a binding partner with DRPLA protein, a product of the gene responsible for a neurodegenerative disorder, dentatorubral pallidoluysian atrophy, as well as a binding partner with brain-specific angiogenesis inhibitor 1. Previous studies identified at least four isoforms (L-, M-, S-and T-forms) in human, where 511 amino acid residues from the N-terminus were identical, followed by unique sequences of 9-41 amino acid residues. As each isoform had a distinct function, the unique sequences at the C-terminus had a vital role in its function. Here we report that these isoforms were indeed generated by alternative splicing, which was established by experimental and computational studies on human and rodent genomes. Previous biochemical reports suggested that rodents may lack one of the isoforms (L-form). This study solved this issue, as a nucleotide substitution occurred at a splice donor site followed by a large deletion in the rodent genome compared with human, which made the generation of the L-form impossible. This study also revealed overlapping of the IRSp53 and AATK genes coded for by complementary strands.

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AATYK: A novel tyrosine kinase induced during growth arrest and apoptosis of myeloid cells

Cited by 70 publications

References 17 publications

Apoptosis-associated tyrosine kinase 1 inhibits growth and migration and promotes apoptosis in melanoma

Apoptosis-associated tyrosine kinase 1 inhibits growth and migration and promotes apoptosis in melanoma

Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression

Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein

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