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TNK2

{{Short description|Protein-coding gene in the species Homo sapiens}}

{{Infobox_gene}}

Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene.

{{cite journal |vauthors=Mahajan K, Mahajan NP | title = Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. | journal = J. Cell. Physiol. | volume = 224 | issue = 2 | pages = 327–23 |date=August 2010 | pmid = 20432460 | pmc = 3953130| doi = 10.1002/jcp.22162 }}{{cite journal |vauthors=Manser E, Leung T, Salihuddin H, Tan L, Lim L | title = A non-receptor tyrosine kinase that inhibits the GTPase activity of p21cdc42 | journal = Nature | volume = 363 | issue = 6427 | pages = 364–7 |date=June 1993 | pmid = 8497321 | doi = 10.1038/363364a0 | bibcode = 1993Natur.363..364M | s2cid = 4307094 }}{{cite journal |vauthors=Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP | title = Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation | journal = PLOS ONE | volume = 5| issue = 3 | pages = e9646|date=March 2010 | pmid = 20333297 | doi = 10.1371/journal.pone.0009646 | pmc=2841635| bibcode = 2010PLoSO...5.9646M | doi-access = free }}{{cite journal |vauthors=Yokoyama N, Miller WT | title = Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck | journal = J Biol Chem | volume = 278 | issue = 48 | pages = 47713–23 |date=November 2003 | pmid = 14506255 | doi = 10.1074/jbc.M306716200 | doi-access = free }}

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.{{cite web | title = Entrez Gene: TNK2 tyrosine kinase, non-receptor, 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10188}}

Interactions

ACK1 or TNK2 has been shown to interact with AKT, Androgen receptor or AR,{{cite journal |vauthors=Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE | title = Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. | journal = Proc Natl Acad Sci U S A | volume = 104| issue = 20 | pages = 8438–43|date=May 2007 | pmid = 17494760 | doi = 10.1073/pnas.0700420104 | pmc=1895968| bibcode = 2007PNAS..104.8438M | doi-access = free }} a tumor suppressor WWOX,{{cite journal |vauthors=Mahajan NP, Whang YE, Mohler JL, Earp HS | title = Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. | journal = Cancer Res. | volume = 65| issue = 22 | pages = 10514–23|date=November 2005 | pmid = 16288044 | doi = 10.1158/0008-5472.can-05-1127| doi-access = free }} FYN{{cite journal |vauthors=Linseman DA, Heidenreich KA, Fisher SK | title = Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway | journal = J. Biol. Chem. | volume = 276 | issue = 8 | pages = 5622–8 |date=February 2001 | pmid = 11087735 | doi = 10.1074/jbc.M006812200 | doi-access = free }} and Grb2.{{cite journal |vauthors=Satoh T, Kato J, Nishida K, Kaziro Y | title = Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation | journal = FEBS Lett. | volume = 386 | issue = 2–3 | pages = 230–4 |date=May 1996 | pmid = 8647288 | doi = 10.1016/0014-5793(96)00449-8 | s2cid = 23523548 | doi-access = free }}{{cite journal |vauthors=Kato-Stankiewicz J, Ueda S, Kataoka T, Kaziro Y, Satoh T | title = Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner | journal = Biochem. Biophys. Res. Commun. | volume = 284 | issue = 2 | pages = 470–7 |date=June 2001 | pmid = 11394904 | doi = 10.1006/bbrc.2001.5004 }} 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,{{cite journal |vauthors=Mahajan K, Coppola D, Rawal B, Chen YA, Lawrence HR, Engelman RW, Lawrence NJ, Mahajan NP | title = Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. | journal = J Biol Chem | volume = 287| issue = 26 | pages = 22112–22|date=June 2012 | pmid = 22566699 | doi = 10.1074/jbc.M112.357384 | pmc=3381169| doi-access = free }}

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.{{cite journal |vauthors=Mahajan K, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP | title = Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. | journal = Am J Pathol | volume = 180| issue = 4 | pages = 1386–93|date=April 2012 | pmid = 22322295 | doi = 10.1016/j.ajpath.2011.12.028 | pmc=3349895}} 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.{{cite journal |vauthors=Lawrence HR, Mahajan K, Luo Y, Zhang D, Tindall N, Huseyin M, Gevariya H, Kazi S, Ozcan S, Mahajan NP, Lawrence NJ | title = Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. | journal = J Med Chem | volume = 58| issue = 6 | pages = 2746–63|date=March 2015 | pmid = 25699576 | doi = 10.1021/jm501929n | pmc=4605435}}

{{cite journal |vauthors=Mahajan K, Mahajan NP | title = PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics. | journal = J. Cell. Physiol. | volume = 227| issue = 9 | pages = 3178–84|date=September 2012 | pmid = 22307544 | doi = 10.1002/jcp.24065 | pmc=3358464}}{{cite journal |vauthors=Mahajan K, Mahajan NP | title = ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation. | journal = Cancer Lett. | volume = 338| issue = 2| pages = 185–92|date=April 2013 | pmid = 23597703 | doi = 10.1016/j.canlet.2013.04.004 | pmc=3750075}} 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

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  • {{cite journal |vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
  • {{cite journal |vauthors=Satoh T, Kato J, Nishida K, Kaziro Y |title=Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation |journal=FEBS Lett. |volume=386 |issue= 2–3 |pages= 230–4 |year= 1996 |pmid= 8647288 |doi=10.1016/0014-5793(96)00449-8 |s2cid=23523548 |doi-access=free }}
  • {{cite journal |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 }}
  • {{cite journal |vauthors=Mott HR, Owen D, Nietlispach D, etal |title=Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK |journal=Nature |volume=399 |issue= 6734 |pages= 384–8 |year= 1999 |pmid= 10360579 |doi= 10.1038/20732 |bibcode=1999Natur.399..384M |s2cid=4313328 }}
  • {{cite journal |vauthors=Eisenmann KM, McCarthy JB, Simpson MA, etal |title=Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas |journal=Nat. Cell Biol. |volume=1 |issue= 8 |pages= 507–13 |year= 2000 |pmid= 10587647 |doi= 10.1038/70302 |s2cid=16876663 |url=http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1018&context=biochemfacpub }}
  • {{cite journal |vauthors=Kato J, Kaziro Y, Satoh T |title=Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation |journal=Biochem. Biophys. Res. Commun. |volume=268 |issue= 1 |pages= 141–7 |year= 2000 |pmid= 10652228 |doi= 10.1006/bbrc.2000.2106 }}
  • {{cite journal |vauthors=Owen D, Mott HR, Laue ED, Lowe PN |title=Residues in Cdc42 that specify binding to individual CRIB effector proteins |journal=Biochemistry |volume=39 |issue= 6 |pages= 1243–50 |year= 2000 |pmid= 10684602 |doi=10.1021/bi991567z }}
  • {{cite journal |vauthors=Kiyono M, Kato J, Kataoka T, etal |title=Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1 |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29788–93 |year= 2000 |pmid= 10882715 |doi= 10.1074/jbc.M001378200 |doi-access= free }}
  • {{cite journal |vauthors=Linseman DA, Heidenreich KA, Fisher SK |title=Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway |journal=J. Biol. Chem. |volume=276 |issue= 8 |pages= 5622–8 |year= 2001 |pmid= 11087735 |doi= 10.1074/jbc.M006812200 |doi-access= free }}
  • {{cite journal |vauthors=Teo M, Tan L, Lim L, Manser E |title=The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors |journal=J. Biol. Chem. |volume=276 |issue= 21 |pages= 18392–8 |year= 2001 |pmid= 11278436 |doi= 10.1074/jbc.M008795200 |doi-access= free }}
  • {{cite journal |vauthors=Kato-Stankiewicz J, Ueda S, Kataoka T, etal |title=Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner |journal=Biochem. Biophys. Res. Commun. |volume=284 |issue= 2 |pages= 470–7 |year= 2001 |pmid= 11394904 |doi= 10.1006/bbrc.2001.5004 }}
  • {{cite journal |vauthors=Oda T, Muramatsu MA, Isogai T, etal |title=HSH2: a novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells |journal=Biochem. Biophys. Res. Commun. |volume=288 |issue= 5 |pages= 1078–86 |year= 2001 |pmid= 11700021 |doi= 10.1006/bbrc.2001.5890 }}
  • {{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |doi-access=free }}
  • {{cite journal |vauthors=Salomon AR, Ficarro SB, Brill LM, etal |title=Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 2 |pages= 443–8 |year= 2003 |pmid= 12522270 |doi= 10.1073/pnas.2436191100 | pmc=141014 |bibcode=2003PNAS..100..443S |doi-access=free }}
  • {{cite journal |vauthors=Ahmed I, Calle Y, Sayed MA, etal |title=Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase, ACK |journal=Biochem. Biophys. Res. Commun. |volume=314 |issue= 2 |pages= 571–9 |year= 2004 |pmid= 14733946 |doi=10.1016/j.bbrc.2003.12.137 }}
  • {{cite journal |vauthors=Gu Y, Lin Q, Childress C, Yang W |title=Identification of the region in Cdc42 that confers the binding specificity to activated Cdc42-associated kinase |journal=J. Biol. Chem. |volume=279 |issue= 29 |pages= 30507–13 |year= 2004 |pmid= 15123659 |doi= 10.1074/jbc.M313518200 |doi-access= free }}
  • {{cite journal |vauthors=Brandenberger R, Wei H, Zhang S, etal |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707–16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 |s2cid=27764390 }}
  • {{cite journal |vauthors=Lougheed JC, Chen RH, Mak P, Stout TJ |title=Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1 |journal=J. Biol. Chem. |volume=279 |issue= 42 |pages= 44039–45 |year= 2004 |pmid= 15308621 |doi= 10.1074/jbc.M406703200 |doi-access= free }}

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External links

  • {{UCSC genome browser|TNK2}}
  • {{UCSC gene details|TNK2}}

{{PDB Gallery|geneid=10188}}

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Category:Tyrosine kinases