Characterization of the apoptosis-associated tyrosine kinase (AATYK) expressed in the CNS

Tomomura, Mineko; Fernandez-Gonzales, A; Yano, Ryoji; Yuzaki, Michisuke

doi:10.1038/sj.onc.1204210

Cited by 35 publications

(50 citation statements)

References 45 publications

(54 reference statements)

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“…Although AATK regulates neuronal differentiation, so-called 'dedifferentiation' is observed in metastatic melanoma. Although AATK is expressed at very low, almost undetectable levels in other tissues except for brain as reported, 9 it is detected at a relatively high level in human melanocytes and a moderate level in several melanoma cell lines derived from primary (non-metastatic) melanomas (Figure 1). The downregulation of AATK expression observed in cell lines derived from metastatic melanomas compared with cell lines derived from primary melanomas and melanocytes suggested a possible role in tumor progression of melanoma.…”

Section: Discussionmentioning

confidence: 97%

“…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. 8 Src is a member of the Src family kinases), which regulate multiple biological processes including cell proliferation, survival, adhesion, and migration, depending on the cellular context.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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

Rubin

2014

Laboratory Investigation

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“…The LMTK1 alanine mutant and the phosphorylation-mimic aspartic acid mutant at Ser34 have been described Tsutsumi et al, 2010). The LMTK1 kinase-deficient mutant (D206V) has been described (Tomomura et al, 2001). pEGFP-Rab5A, pEGFP-Rab7, pEGFPRab11A, and pEF-T7-FIP2C have been described (Fukuda, 2003;Fukuda et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…We next examined whether LMTK1 regulates axonal outgrowth through its kinase activity using the kinasenegative mutant LMTK1-D206V (Tomomura et al, 2001). The overexpression of LMTK1-D206V increased axon length (265 Ϯ 17 m) by 1.9-fold compared with axons from neurons transfected with LMTK1-WT (142 Ϯ 8 m) (Fig.…”

Section: Effect Of Phosphorylation Of Lmtk1 At Ser34 On Axonal Outgrowthmentioning

confidence: 99%

LMTK1/AATYK1 Is a Novel Regulator of Axonal Outgrowth That Acts via Rab11 in a Cdk5-Dependent Manner

et al. 2012

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Axonal outgrowth is a coordinated process of cytoskeletal dynamics and membrane trafficking; however, little is known about proteins responsible for regulating the membrane supply. LMTK1 (lemur kinase 1)/AATYK1 (apoptosis-associated tyrosine kinase 1) is a serine/ threonine kinase that is highly expressed in neurons. We recently reported that LMTK1 plays a role in recycling endosomal trafficking in CHO-K1 cells. Here we explore the role of LMTK1 in axonal outgrowth and its regulation by Cdk5 using mouse brain cortical neurons. LMTK1 was expressed and was phosphorylated at Ser34, the Cdk5 phosphorylation site, at the time of axonal outgrowth in culture and colocalized with Rab11A, the small GTPase that regulates recycling endosome traffic, at the perinuclear region and in the axon. Overexpression of the unphosphorylated mutant LMTK1-S34A dramatically promoted axonal outgrowth in cultured neurons. Enhanced axonal outgrowth was diminished by the inactivation of Rab11A, placing LMTK1 upstream of Rab11A. Unexpectedly, the downregulation of LMTK1 by knockdown or gene targeting also significantly enhanced axonal elongation. Rab11A-positive vesicles were transported anterogradely more quickly in the axons of LMTK1-deficient neurons than in those of wild-type neurons. The enhanced axonal outgrowth was reversed by LMTK1-WT or the LMTK1-S34D mutant, which mimics the phosphorylated state, but not by LMTK1-S34A. Thus, LMTK1 can negatively control axonal outgrowth by regulating Rab11A activity in a Cdk5-dependent manner, and Cdk5-LMTK1-Rab11 is a novel signaling pathway involved in axonal outgrowth.

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“…Aatyk1 is preferentially expressed in brain (9,10), and several potential roles have been proposed in the nervous system, including regulation of neural differentiation (10) and apoptosis (11,12). However, these potential roles were evaluated with in vitro experiments only, and definitive evidence for the role of Aatyk1 has not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Azoospermia in mice with targeted disruption of theBrek/Lmtk2(brain-enriched kinase/lemur tyrosine kinase 2) gene

Kawa¹,

Ito

Toyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Brek/Lmtk2 (brain-enriched kinase/lemur tyrosine kinase 2) is a member of the Aatyk family of kinases that comprises Aatyk1, Brek/Lmtk2/Aatyk2, and Aatyk3. Although several potential roles have been proposed for Brek and other Aatyk family members, the physiological functions of these kinases remain unclear. Here, we report that Brek ؊/؊ male mice are infertile, with azoospermia. Detailed histological analysis revealed that Brek ؊/؊ germ cells differentiated normally until the round-spermatid stage, but failed to undergo the normal change in morphology to become elongated spermatids. Testicular somatic cells appeared normal in these mice. Expression of Brek in testis was restricted to the germ cells, suggesting that the maturations of germ cells in Brek ؊/؊ mice are affected in a cell-autonomous manner. On the basis of these findings, we concluded that Brek is essential for a late stage of spermatogenesis. Further clarification of the mechanism by which Brek regulates spermatogenesis may help identify new targets for reproductive contraceptives and treatments against infertility.AATYK ͉ BREK ͉ infertility ͉ LMTK2 ͉ spermatogenesis S permatogenesis, the process by which primordial germ cells generate sperm, is a complex process that includes mitotic division of spermatogonia, meiotic division of spermatocytes to generate haploid cells called spermatids, and differentiation of the spermatids into sperm cells. The last maturation step in which haploid spermatids undergo a complex restructuring program is called spermiogenesis. Spermiogenesis begins with formation of the acrosome from Golgi-derived vesicles, followed by formation of a flagellum, condensation of the nucleus with DNA compaction, and jettison of the cytoplasm. The resulting mature sperm consists of a head with a nucleus and a tail and enters the lumen of the seminiferous tubules. Spermatozoa that differentiate in the testis mature further during the passage through the epididymal duct to acquire functions essential for fertilization.Protein-phosphorylation events play pivotal roles in regulating intracellular signals in response to a wide variety of stimuli. There is accumulating evidence that protein kinases, such as c-Kit, play critical and distinct roles in spermatogenesis (1). Brek (brain-enriched kinase) is a member of the protein kinase subfamily that comprises Aatyk1, Brek/Lmtk2/Aatyk2, and Aatyk3. This kinase subfamily was recently identified through a genome database search for human tyrosine kinases and was tentatively named the Aatyk (apoptosis-associated tyrosine kinase) subfamily (2). Generation of a phyletic tree of known tyrosine and Ser/Thr kinases revealed that Aatyk family kinases represent a previously uncharacterized category of kinases that reside between tyrosine kinases and Ser/Thr kinases. The primary structures of Aatyk kinases show slightly higher homology to tyrosine kinases than to Ser/Thr kinases, but we previously showed that the Aatyk kinases are Ser/Thr kinases and not tyrosine kinases (3). Although Brek is also called A...

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Characterization of the apoptosis-associated tyrosine kinase (AATYK) expressed in the CNS

Cited by 35 publications

References 45 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

LMTK1/AATYK1 Is a Novel Regulator of Axonal Outgrowth That Acts via Rab11 in a Cdk5-Dependent Manner

Azoospermia in mice with targeted disruption of theBrek/Lmtk2(brain-enriched kinase/lemur tyrosine kinase 2) gene

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