Apoptosis Associated Tyrosine Kinase (AATYK), a novel protein recently isolated from differentiating 32D mouse myeloid cells, contains a putative tyrosine kinase domain and several binding motifs for src homology 2 (SH-2) and src homology 3 (SH-3) domain containing proteins. We observed that AATYK is expressed in different regions of the brain. Although it might play a role in normal nervous system development by modulating apoptosis, little is known regarding its function in the brain or its intracellular localization and kinase activity. Recognizing its homology with Insulin like growth factor-I (IGF-I) receptor (IGF-IR) and the critical role of IGF-I in neuronal survival, we hypothesized that AATYK plays an important role in neuronal differentiation/apoptosis. To test this hypothesis, we transfected the human adrenergic neuroblastoma (NB):SH-SY5Y cells with AATYK cDNA under a tetracycline-repressible promoter and established stable cell lines that readily express AATYK on removal of tetracycline. AATYK immunoprecipitated from these cell lysates is an active kinase. Indirect immunofluorescent staining of the clones revealed AATYK to be localized in the cytoplasm. By itself, AATYK overexpression for short duration (2-3 days) did not induce differentiation in the stable SH-SY5Y clones. On the other hand, overexpression for longer periods (7-8 days) per se, significantly (P<0.05-0.001) increased the percent of differentiated cells as well as the neurite length. AATYK-induced differentiation was in the same range as the differentiation induced by agents like all-trans retinoic acid (RA), 12-O-Tetradecanoyl phorbol 13-acetate (TPA) and IGF-I. In addition, AATYK significantly promoted the neuronal differentiation induced by these agents. Our results demonstrate for the first time that AATYK is an active, non-receptor, cytosolic kinase which induces neuronal differentiation and also promotes differentiation induced by other agents in the SH-SY5Y cells.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
A 3(')-terminal fragment of a splice variant of KIAA0641, a human homologue of apoptosis-associated tyrosine kinase (AATYK), was screened from human brain cDNA libraries by a yeast two-hybrid system using a Cdk5 activator p35 as a bait. The cloned cDNA encoded 477 amino acids, composed of internal 458 amino acids of KIAA0641 and 19 amino acids unique to this variant after splicing, then referred to this clone as hAATYKs-p35BP (human AATYK short isoform-p35 binding polypeptide). Using GST-fusion protein, hAATYKs-p35BP was shown to bind to Cdk5/p35 in a rat brain extract. hAATYKs made by fusing the kinase domain of KIAA0641 to the N-terminus of hAATYKs-p35BP was used for binding to Cdk5/p35 in HEK293 cells. Both hAATYKs and KIAA0641 bound to and were phosphorylated by Cdk5/p35. These results suggest that both isoforms of hAATYK are novel Cdk5/p35-binding and substrate proteins.
A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathways) which typically lead to rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. The process ends when the cell has died. The process is divided into a signaling pathway phase, and an execution phase, which is triggered by the former.
Protein which catalyzes the phosphorylation of serine or threonine residues on target proteins by using ATP as phosphate donor. Such phosphorylation may cause changes in the function of the target protein. Protein kinases share a conserved catalytic core common to both serine/ threonine and tyrosine protein kinases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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