Tnk1

Beyond the most common oncogenes activated by mutation (mut-drivers) there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and post-translational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function...

Human thirty-eight-negative kinase-1 (TNK1) is implicated in cancer progression. The TNK1 ubiquitin-associated (UBA) domain binds polyubiquitin and plays a regulatory role in TNK1 activity and stability. No experimentally determined molecular structure of this unusual UBA domain is available. We fused the UBA domain to the 1TEL variant of the translocation ETS leukemia protein sterile alpha motif (TELSAM) crystallization chaperone and obtained crystals diffracting as far as 1.53 Å. GG and GSGG linkers allowed the UBA to reproducibly find a productive binding mode against its host 1TEL polymer and crystallize at protein concentrations as low as 0...

Human thirty-eight-negative kinase-1 (TNK1) is implicated in cancer progression. The TNK1-UBA domain binds polyubiquitin and plays a regulatory role in TNK1 activity and stability. Sequence analysis suggests an unusual architecture for the TNK1 UBA domain, but an experimentally-validated molecular structure is undetermined. To gain insight into TNK1 regulation, we fused the UBA domain to the 1TEL crystallization chaperone and obtained crystals diffracting as far as 1.53 Å. A 1TEL search model enabled solution of the X-ray phases...

14-3-3s are abundant proteins that regulate essentially all aspects of cell biology, including cell cycle, motility, metabolism, and cell death. 14-3-3s work by docking to phosphorylated Ser/Thr residues on a large network of client proteins and modulating client protein function in a variety of ways. In recent years, aided by improvements in proteomics, the discovery of 14-3-3 client proteins has far outpaced our ability to understand the biological impact of individual 14-3-3 interactions. The rate-limiting step in this process is often the identification of the individual phospho-serines/threonines that mediate 14-3-3 binding, which are difficult to distinguish from other phospho-sites by sequence alone...

Human Tnk1 (thirty-eight-negative kinase 1) is a member of the Ack family of nonreceptor tyrosine kinases. Tnk1 contains a sterile alpha motif (SAM), a tyrosine kinase catalytic domain, an SH3 (Src homology 3) domain, and a large C-terminal region that contains a ubiquitin association domain. However, specific physiological roles for Tnk1 have nopt been characterized in depth. Here, we expressed and purified Tnk1 from Sf9 insect cells and established an in vitro assay system using a peptide substrate derived from the Wiskott-Aldrich Syndrome Protein (WASP)...

Thirty-eight-negative kinase 1 (TNK1) is a poorly characterized non-receptor tyrosine kinase (NRTK) first isolated from umbilical cord blood. TNK1 differs from most NRTKs in that it possesses a functional ubiquitin association (UBA) domain at its C-terminus. We previously observed that the TNK1 UBA domain interacts with a variety of poly-ubiquitin chains, is essential for full TNK1 activation, and facilitates the clustering of active TNK1 into ubiquitin-rich condensates.1 Paradoxically, a genetic inversion that truncates the TNK1 C-terminus (including the UBA domain) in human lymphoma hyperactivates the kinase and coverts it into an oncogenic driver...

We recently developed a machine learning (ML) based program to predict cancer hotspots. Here, we applied the ML program to 32 non-receptor tyrosine kinases (NRTKs) and identified 36 potential cancer driver mutations, with high probability mutations in 10 genes, including ABL1, ABL2, JAK1, JAK3, and ACK1. Interestingly among all the NRTKs, ACK1 is the only kinase that, when altered, shows a significant drop in overall survival, supporting the idea that ACK1 is an oncogenic tyrosine kinase. ACK1 is a member of the poorly understood ACK family of NRTKs that also includes TNK1...

Thirty-eight negative kinase-1 (TNK1) is an understudied non-receptor tyrosine kinase with no established function or mechanism of regulation. We recently identified TNK1 as the primary kinase driver of cell survival in subsets of patient blood cancer samples1 . We discovered that one unusual feature of TNK1 is a functional ubiquitin-association (UBA) domain that binds with high affinity to multiple poly-ubiquitin linkages. Our recent 1.5 angstrom crystal structure of the TNK1 UBA shows an atypical five-helix UBA domain with two predicted ubiquitin-binding interfaces...

Thirty -eight negative kinase 1 (TNK1) is a poorly characterized member of the ACK family of non-receptor tyrosine kinases. Previous studies suggest a role for TNK1 in oncogenic transformation; however, the biological function, regulation and substrates of TNK1 remain unknown. We previously discovered that the phospho-binding protein 14-3-3 binds to a phospho-serine (S502) within a C-terminal proline-rich domain of TNK1, sequestering TNK1 in the cytosol and inhibiting its kinase activity. Conversely, the release of TNK1 from 14-3-3 activates TNK1 and increases its oncogenic activity1 ...

Thirty-eight-negative kinase 1 (TNK1) is a poorly understood member of the ACK family of non-receptor tyrosine kinases. TNK1 has been linked to oncogenic activity. However, the biological function of TNK1 remains unclear. Recently, we discovered the presence of a functional ubiquitin association (UBA) domain on the C-terminus of TNK1, which is an unusual feature on a kinase. Previously, we demonstrated that the TNK1 UBA domain binds to poly-ubiquitin with high affinity and with no preference for length or linkage type (1)...

TNK1 is a poorly understood non-receptor tyrosine kinase that by mutation can be converted into an oncogenic driver. While little is known about the normal function of TNK1, it possesses a C-terminal ubiquitin binding domain (UBA) that interacts with high affinity to multiple poly-ubiquitin linkages. To our knowledge, this ability to directly interact with poly-ubiquitin makes TNK1 unique across the human kinome. Our recent data suggest that the UBA domain of TNK1 homes the kinase to phase-separated condensates of poly-ubiquitinated proteins where TNK1 becomes fully active...

Hemorrhage shock (HS) is a major threat to patients with trauma and spontaneous bleeding, resulting in multi-organ failure including the kidney. Tyrosine kinase nonreceptor 1 (TNK1) has been shown to be upregulated in the kidney of experimental HS and patients with severe trauma . The study aims to investigate the role of TNK1 and the underlying mechanism in HS-induced kidney injury. A model of HS was established with femoral artery bloodletting, followed by resuscitation in Sprague-Dawley rats. Renal expression of TNK1 was abnormally induced by HS in rats...

TNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify TNK1 dependencies in primary human cancers. We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity. Conversely, the release of TNK1 from 14-3-3 allows TNK1 to cluster in ubiquitin-rich puncta and become active. Active TNK1 induces growth factor-independent proliferation of lymphoid cells in cell culture and mouse models...

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing...

TNK1 (thirty-eight-negative kinase 1) belongs to the ACK (Activated Cdc42 Kinases) family of intracellular non-receptor tyrosine kinases that usually acts as an important regulator in cytokine receptor-mediated intracellular signal transduction pathways. JAK-STAT signal pathway acts as a key point in cellular proliferation, differentiation and immunomodulatory. Mammalian TNK1 is involved in antiviral immunity and activation of growth factors. However, TNK1 has rarely been studied in fish. To evaluate the role of fish TNK1 in JAK-STAT pathway, we cloned the full-length cDNA sequence of grass carp (Ctenopharyngodon idella) TNK1 (CiTNK1)...

Several single-nucleotide polymorphisms (SNPs) and rare variants of non-receptor tyrosine kinase 1 gene (TNK1) have been associated with Alzheimer's disease (AD). To date, none of the associations have proven to be of practical importance in predicting the risk of AD either because the evidence is not conclusive, or the risk alleles occur at very low frequency. In the present study, we are evaluating the associations between rs11867353 polymorphism of TNK1 gene and both AD and mild cognitive impairment (MCI) in a group of 1656 persons...

Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation...

BACKGROUND: Bladder cancer is the tenth most common cancer globally, but existing biomarkers and prognostic models are limited. METHOD: In this study, we used four bladder cancer cohorts from The Cancer Genome Atlas and Gene Expression Omnibus databases to perform univariate Cox regression analysis to identify common prognostic genes. We used the least absolute shrinkage and selection operator regression to construct a prognostic Cox model. Kaplan-Meier analysis, receiver operating characteristic curve, and univariate/multivariate Cox analysis were used to evaluate the prognostic model...

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. METHODS: The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis...

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41-76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history...