TNK2

Last updated • 9 min readFrom Wikipedia, The Free Encyclopedia
TNK2
Protein TNK2 PDB 1cf4.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNK2 , ACK, ACK-1, ACK1, p21cdc42Hs, tyrosine kinase non receptor 2
External IDs OMIM: 606994 MGI: 1858308 HomoloGene: 4224 GeneCards: TNK2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene. [5] [6] [7] [8] [9] 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. [9]

Interactions

ACK1 or TNK2 has been shown to interact with AKT, [7] Androgen receptor or AR, [10] a tumor suppressor WWOX, [11] FYN [12] and Grb2. [13] [14] 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, [15]

Clinical relevance

ACK1 is a survival kinase and shown to be associated with tumor cell survival, proliferation, hormone-resistance and radiation resistance. [5] The activation of ACK1 has been observed in prostate, breast, pancreatic, lung and ovarian cancer cells. [5] [7] [10] [16] ACK1 transgenic mice, expressing activated ACK1 specifically in prostate gland has been reported; these mice develop prostatic intraepithelial neoplasia (PINs). [7]

ACK1 inhibitors

Ack1 has emerged as a new cancer target and multiple small molecule inhibitors have been reported. [17] [18] [19] 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

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000061938 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022791 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Mahajan K, Mahajan NP (August 2010). "Shepherding AKT and androgen receptor by Ack1 tyrosine kinase". J. Cell. Physiol. 224 (2): 327–23. doi:10.1002/jcp.22162. PMC   3953130 . PMID   20432460.
  6. Manser E, Leung T, Salihuddin H, Tan L, Lim L (June 1993). "A non-receptor tyrosine kinase that inhibits the GTPase activity of p21cdc42". Nature. 363 (6427): 364–7. Bibcode:1993Natur.363..364M. doi:10.1038/363364a0. PMID   8497321. S2CID   4307094.
  7. 1 2 3 4 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 (March 2010). "Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation". PLOS ONE. 5 (3): e9646. Bibcode:2010PLoSO...5.9646M. doi: 10.1371/journal.pone.0009646 . PMC   2841635 . PMID   20333297.
  8. Yokoyama N, Miller WT (November 2003). "Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck". J Biol Chem. 278 (48): 47713–23. doi: 10.1074/jbc.M306716200 . PMID   14506255.
  9. 1 2 "Entrez Gene: TNK2 tyrosine kinase, non-receptor, 2".
  10. 1 2 Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE (May 2007). "Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation". Proc Natl Acad Sci U S A. 104 (20): 8438–43. Bibcode:2007PNAS..104.8438M. doi: 10.1073/pnas.0700420104 . PMC   1895968 . PMID   17494760.
  11. Mahajan NP, Whang YE, Mohler JL, Earp HS (November 2005). "Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox". Cancer Res. 65 (22): 10514–23. doi: 10.1158/0008-5472.can-05-1127 . PMID   16288044.
  12. Linseman DA, Heidenreich KA, Fisher SK (February 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.
  13. Satoh T, Kato J, Nishida K, Kaziro Y (May 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.
  14. Kato-Stankiewicz J, Ueda S, Kataoka T, Kaziro Y, Satoh T (June 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.
  15. Mahajan K, Coppola D, Rawal B, Chen YA, Lawrence HR, Engelman RW, Lawrence NJ, Mahajan NP (June 2012). "Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer". J Biol Chem. 287 (26): 22112–22. doi: 10.1074/jbc.M112.357384 . PMC   3381169 . PMID   22566699.
  16. Mahajan K, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP (April 2012). "Ack1 tyrosine kinase activation correlates with pancreatic cancer progression". Am J Pathol. 180 (4): 1386–93. doi:10.1016/j.ajpath.2011.12.028. PMC   3349895 . PMID   22322295.
  17. Lawrence HR, Mahajan K, Luo Y, Zhang D, Tindall N, Huseyin M, Gevariya H, Kazi S, Ozcan S, Mahajan NP, Lawrence NJ (March 2015). "Development of novel ACK1/TNK2 inhibitors using a fragment-based approach". J Med Chem. 58 (6): 2746–63. doi:10.1021/jm501929n. PMC   4605435 . PMID   25699576.
  18. Mahajan K, Mahajan NP (September 2012). "PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics". J. Cell. Physiol. 227 (9): 3178–84. doi:10.1002/jcp.24065. PMC   3358464 . PMID   22307544.
  19. Mahajan K, Mahajan NP (April 2013). "ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation". Cancer Lett. 338 (2): 185–92. doi:10.1016/j.canlet.2013.04.004. PMC   3750075 . PMID   23597703.

Further reading

Related Research Articles

<span class="mw-page-title-main">ABL (gene)</span> Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

<span class="mw-page-title-main">Cortactin</span> Protein found in humans

Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.

<span class="mw-page-title-main">Adapter molecule crk</span> Protein-coding gene in the species Homo sapiens

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

<span class="mw-page-title-main">Janus kinase 1</span>

JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.

<span class="mw-page-title-main">FYN</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.

<span class="mw-page-title-main">PIK3R1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.

<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

Cbl is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

<span class="mw-page-title-main">Fibroblast growth factor receptor 4</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.

<span class="mw-page-title-main">STAT5A</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.

<span class="mw-page-title-main">PTK2B</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.

<span class="mw-page-title-main">FRS2</span> Protein-coding gene in humans

Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.

<span class="mw-page-title-main">BCAR1</span> Protein-coding gene in the species Homo sapiens

Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.

<span class="mw-page-title-main">EPH receptor A2</span> Protein-coding gene in humans

EPH receptor A2 is a protein that in humans is encoded by the EPHA2 gene.

<span class="mw-page-title-main">Protein kinase D1</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase D1 is an enzyme that in humans is encoded by the PRKD1 gene.

<span class="mw-page-title-main">PTPRA</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase alpha is an enzyme that in humans is encoded by the PTPRA gene.

<span class="mw-page-title-main">BMX (gene)</span> Type of enzyme

Cytoplasmic tyrosine-protein kinase BMX is an enzyme that in humans is encoded by the BMX gene.

<span class="mw-page-title-main">Discoidin domain-containing receptor 2</span> Protein-coding gene in the species Homo sapiens

Discoidin domain-containing receptor 2, also known as CD167b, is a protein that in humans is encoded by the DDR2 gene. Discoidin domain-containing receptor 2 is a receptor tyrosine kinase (RTK).

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.