Structural and functional analysis of the apoptosis-associated tyrosine kinase (AATYK) family

Tomomura, Mineko; Morita, Noriyuki; Yoshikawa, Fumio; Konishi, Akio; Akiyama, Hiroki; Furuichi, Teiichi; Kamiguchi, Hiroyuki

doi:10.1016/j.neuroscience.2007.05.048

Cited by 43 publications

(54 citation statements)

References 35 publications

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“…We recently reported that LMTK1A (lemur kinase 1A)/AATYK1A (apoptosis-associated tyrosine kinase 1A) promotes the formation of Rab11A-positive recycling endosomes in CHO-K1 cells Tsutsumi et al, 2010). LMTK1 is an uncharacterized serine/threonine (Ser/Thr) kinase that is highly expressed in the nervous system (Gaozza et al, 1997;Baker et al, 2001;Tomomura et al, 2007). We hypothesized that LMTK1 participates in axonal outgrowth by regulating Rab11 activity for recycling endosomes.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…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%

“…AATKA encodes a cytoplasmic protein with an open reading frame of 1317 amino acids, whereas AATKB contains an additional transmembrane domain at the N-terminus, which adds 57 amino acids. 4,5 Functional differences between the two isoforms have never been addressed. Most functional studies of AATK have been focused on the nervous system.…”

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“…The expression of AATK is upregulated during neuronal differentiation of P19 embryonal carcinoma cells induced by retinoic acid. 4 Overexpression of exogenous AATK promotes both neuronal differentiation of human neuroblastoma SH-SY5Y cells, 2 neurite extension of immature cerebellar granule cells, 3 and apoptosis of cerebellar granule cells. 4 These results indicate that AATK might have a role in nervous system development by its dual functions of promoting terminal neuronal differentiation of developing neurons and enhancing apoptosis of mature cerebellar granule cells.…”

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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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“…It has 1460 amino acids (a.a) with a catalytic domain of 279 amino acids located between 133 and 411. This kinase appears to serine-threonine-tyrosine kinases family [12][13][14] which has been defined as an essential actor involved in endocrine resistance process [15]. Furthermore, the overexpression of LMTK3 accelerates the dispersion and invasion of tumor cells which are the first steps of the metastatic process [15].…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional Structure Prediction of the Human LMTK3 Catalytic Domain in DYG-in Conformation

Allam¹,

Lakhlili²,

Tarhda³

et al. 2017

J Biomol Res Ther

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Structural and functional analysis of the apoptosis-associated tyrosine kinase (AATYK) family

Cited by 43 publications

References 35 publications

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

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

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

Three-dimensional Structure Prediction of the Human LMTK3 Catalytic Domain in DYG-in Conformation

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