TNK2

Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene. TNK2 gene encodes a non-receptor tyrosine kinase, ACK1, that binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined.

TNK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CF4, 1U46, 1U4D, 1U54, 3EQP, 3EQR, 4EWH, 4HZR, 4HZS, 4ID7
Identifiers
Aliases	TNK2, ACK, ACK-1, ACK1, p21cdc42Hs, tyrosine kinase non receptor 2
External IDs	OMIM: 606994; MGI: 1858308; HomoloGene: 4224; GeneCards: TNK2; OMA:TNK2 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3q29 Start 195,863,364 bp End 195,911,945 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16|16 B3 Start 32,462,692 bp End 32,502,311 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum right frontal lobe cingulate gyrus anterior cingulate cortex amygdala granulocyte nucleus accumbens anterior pituitary Brodmann area 9 putamen Top expressed in medial vestibular nucleus substantia nigra lateral hypothalamus paraventricular nucleus of hypothalamus dorsal tegmental nucleus neural layer of retina deep cerebellar nuclei pontine nuclei dentate gyrus of hippocampal formation granule cell motor neuron More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity epidermal growth factor receptor binding GTPase inhibitor activity metal ion binding kinase activity protein serine/threonine kinase activity protein binding identical protein binding WW domain binding protein tyrosine kinase activity ATP binding ubiquitin protein ligase binding non-membrane spanning protein tyrosine kinase activity protein serine/threonine/tyrosine kinase activity Cellular component endosome membrane extrinsic component of cytoplasmic side of plasma membrane adherens junction plasma membrane cell junction Grb2-EGFR complex clathrin-coated pit cytoplasmic vesicle membrane cytoplasmic vesicle nucleus clathrin-coated vesicle cytoplasm perinuclear region of cytoplasm cytoophidium Biological process cell differentiation endocytosis phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway small GTPase mediated signal transduction protein phosphorylation cell surface receptor signaling pathway regulation of cell population proliferation positive regulation of peptidyl-tyrosine phosphorylation peptidyl-tyrosine autophosphorylation regulation of clathrin-dependent endocytosis innate immune response cell migration negative regulation of GTPase activity signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10188 51789 Ensembl ENSG00000061938 ENSMUSG00000022791 UniProt Q07912 O54967 RefSeq (mRNA) NM_001010938 NM_001308046 NM_005781 NM_001382271 NM_001382272 NM_001382273 NM_001382274 NM_001382275 NM_001110147 NM_001289443 NM_016788 NM_001347185 RefSeq (protein) NP_001010938 NP_001294975 NP_005772 NP_001103617 NP_001276372 NP_001334114 NP_058068 Location (UCSC) Chr 3: 195.86 – 195.91 Mb Chr 16: 32.46 – 32.5 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Interactions

ACK1 or TNK2 has been shown to interact with AKT, Androgen receptor or AR, a tumor suppressor WWOX, FYN and Grb2. ACK1 interaction with its substrates resulted in their phosphorylation at specific tyrosine residues. ACK1 has been shown to directly phosphorylate AKT at tyrosine 176, AR at Tyrosine 267 and 363, and WWOX at tyrosine 287 residues, respectively. ACK1-AR signaling has also been reported to regulate ATM levels,

Clinical relevance

ACK1 is a survival kinase and shown to be associated with tumor cell survival, proliferation, hormone-resistance and radiation resistance. The activation of ACK1 has been observed in prostate, breast, pancreatic, lung and ovarian cancer cells. ACK1 transgenic mice, expressing activated ACK1 specifically in prostate gland has been reported; these mice develop prostatic intraepithelial neoplasia (PINs).

ACK1 inhibitors

Ack1 has emerged as a new cancer target and multiple small molecule inhibitors have been reported. All of these inhibitors are currently in the pre-clinical stage.

Mahajan, K., Malla, P., Lawrence, H. R., Chen, Z., Kumar-Sinha, C., Malik, R., … Mahajan, N. P. (2017). ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer. Cancer Cell, 31(6), 790-803.e8. https://doi.org/10.1016/j.ccell.2017.05.003

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Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Satoh T, Kato J, Nishida K, Kaziro Y (1996). "Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation". FEBS Lett. 386 (2–3): 230–4. doi:10.1016/0014-5793(96)00449-8. PMID 8647288. S2CID 23523548.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Mott HR, Owen D, Nietlispach D, et al. (1999). "Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK". Nature. 399 (6734): 384–8. Bibcode:1999Natur.399..384M. doi:10.1038/20732. PMID 10360579. S2CID 4313328.
• Eisenmann KM, McCarthy JB, Simpson MA, et al. (2000). "Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas". Nat. Cell Biol. 1 (8): 507–13. doi:10.1038/70302. PMID 10587647. S2CID 16876663.
• Kato J, Kaziro Y, Satoh T (2000). "Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation". Biochem. Biophys. Res. Commun. 268 (1): 141–7. doi:10.1006/bbrc.2000.2106. PMID 10652228.
• Owen D, Mott HR, Laue ED, Lowe PN (2000). "Residues in Cdc42 that specify binding to individual CRIB effector proteins". Biochemistry. 39 (6): 1243–50. doi:10.1021/bi991567z. PMID 10684602.
• Kiyono M, Kato J, Kataoka T, et al. (2000). "Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1". J. Biol. Chem. 275 (38): 29788–93. doi:10.1074/jbc.M001378200. PMID 10882715.
• Linseman DA, Heidenreich KA, Fisher SK (2001). "Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway". J. Biol. Chem. 276 (8): 5622–8. doi:10.1074/jbc.M006812200. PMID 11087735.
• Teo M, Tan L, Lim L, Manser E (2001). "The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors". J. Biol. Chem. 276 (21): 18392–8. doi:10.1074/jbc.M008795200. PMID 11278436.
• Kato-Stankiewicz J, Ueda S, Kataoka T, et al. (2001). "Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner". Biochem. Biophys. Res. Commun. 284 (2): 470–7. doi:10.1006/bbrc.2001.5004. PMID 11394904.
• Oda T, Muramatsu MA, Isogai T, et al. (2001). "HSH2: a novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells". Biochem. Biophys. Res. Commun. 288 (5): 1078–86. doi:10.1006/bbrc.2001.5890. PMID 11700021.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Salomon AR, Ficarro SB, Brill LM, et al. (2003). "Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry". Proc. Natl. Acad. Sci. U.S.A. 100 (2): 443–8. Bibcode:2003PNAS..100..443S. doi:10.1073/pnas.2436191100. PMC 141014. PMID 12522270.
• Ahmed I, Calle Y, Sayed MA, et al. (2004). "Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase, ACK". Biochem. Biophys. Res. Commun. 314 (2): 571–9. doi:10.1016/j.bbrc.2003.12.137. PMID 14733946.
• Gu Y, Lin Q, Childress C, Yang W (2004). "Identification of the region in Cdc42 that confers the binding specificity to activated Cdc42-associated kinase". J. Biol. Chem. 279 (29): 30507–13. doi:10.1074/jbc.M313518200. PMID 15123659.
• Brandenberger R, Wei H, Zhang S, et al. (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197. S2CID 27764390.
• Lougheed JC, Chen RH, Mak P, Stout TJ (2004). "Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1". J. Biol. Chem. 279 (42): 44039–45. doi:10.1074/jbc.M406703200. PMID 15308621.

External links

• TNK2 human gene location in the UCSC Genome Browser.
• TNK2 human gene details in the UCSC Genome Browser.