Disease relevance of TNK2 or Ack1 [1]

• Ack1 activation has been reported in prostate [2] [3], breast [4] and pancreatic [5] primary human tumors. Levels of phosphorylated Ack1 correlated with disease progression and inversely correlated with patient survival.
• Somatic mutations in Ack1 have been identified in lung (R34L), ovarian (R99Q, E346K) and stomach (M409I) cancers [4].
• Transgenic mice expressing activated Ack1 specifically in prostates developed prostatic intraepithelial neoplasia (PINs) in about 40 weeks [4].
• Ack1 specific small molecule inhibitor, AIM-100 inhibited growth of various cancer derived cell lines [6] and arrested cells in G1 phase of cell cycle [7].
• Ack1 gene amplification has been observed in breast, lung and prostate cancers [8].
• Overexpression of Ack1 in cancer cell lines increased the invasive phenotype of these cells and leads to increased mortality in a mouse model of metastasis [8]
• Because tyrosine kinase activity is a requirement for neuritogenesis in several cell systems, we investigated whether endogenous mAChRs (principally of the M3 subtype) expressed in human SH-SY5Y neuroblastoma cells would signal to ACK-1 [9].
• ACK-1 phosphorylation was blocked by Clostridium difficile toxin B, an inhibitor of Rho family GTPases [9].
• Further, these findings suggest that Ack1 could be a novel therapeutic target for prostate cancer [10].
• To characterize the enzymatic properties of ACK, we have expressed and purified active ACK using the baculovirus/Sf9 cell system [11].
• Targeting the Ack1 kinase may be a potential therapeutic strategy in prostate cancer [3].

Psychiatry related information on TNK2

• Results point to the superiority of ACK over PRO in substance abuse identification [12].

High impact information on TNK2

• The interaction extends the beta-sheet in Cdc42 by binding an extended strand from ACK, as seen in Ras/effector interactions, but it also involves other regions of the G protein that are important for determining the specificity of effector binding [13].
• Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK [13].
• Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1 [8].
• Biochemical studies show that Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac [8].
• Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr287, suggesting that phosphorylation of distinct tyrosine residues activate or degrade Wwox [10].

Chemical compound and disease context of TNK2

• Specifically, we evaluated the Alcohol/Drug Problem Acknowledgment scale (ACK; Weed, Butcher, & Williams, 1994), the Alcohol/Drug Problem Proneness scale (PRO; Weed et al., 1994), and the MacAndrew Alcoholism Scale-Revised (MAC-R; Butcher et al., 1992) in the prediction of substance abuse [12].

Biological context of TNK2

• Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation [14].
• ACK1 is known to bind clathrin and influence EGF receptor endocytosis [15].
• Biotinylated SH3 domains were also used for specific identification of target proline-rich sequences in synaptojanin and ACK1 on synthetic peptides arrays [15].
• Although stimulation of M3 mAChRs induces both an increase in intracellular Ca2+ and activation of protein kinase C (PKC), neither of these second messenger pathways was required for receptor-stimulated ACK-1 phosphorylation [9].
• Overexpression of ACK42 (a Cdc42 binding domain of ACK) inhibited cell growth and movement, indicating that Cdc42 signals are transduced to the nucleus through ACKs [16].

Anatomical context of TNK2

• In contrast, disruption of the actin cytoskeleton with cytochalasin D stimulated ACK-1 phosphorylation, and moreover, addition of Oxo-M to cells preincubated with this agent elicited a further increase in phosphorylation, indicating that an intact cytoskeleton is not required for mAChR signaling to ACK-1 [9].
• We show here that activated ACK1, a nonreceptor tyrosine kinase that belongs to the focal adhesion kinase family, causes tyrosine phosphorylation of Ras-GRF1 [17].
• In addition, we show that EGF transiently induces formation of the focal complex and stress fibers when ACK1 was ectopically expressed [18].
• It is demonstrated that TNK2 exerts normal NK activity and displays large granular lymphocyte morphology [19].
• Stable low level expression of green fluorescent protein-ACK1 in NIH 3T3 cells has been used to localize ACK1 to clathrin-containing vesicles [20].

Associations of TNK2 with chemical compounds

• Finally, scrape loading cells with glutathione S-transferase fusion proteins of either the Fyn-SH2 or Fyn-SH3 domain significantly attenuated mAChR-stimulated ACK-1 tyrosine phosphorylation [9].
• Incubation of cells with the cholinergic agonist oxotremorine-M (Oxo-M) induced an approximately 6-fold increase in the tyrosine phosphorylation of ACK-1 which was inhibited by atropine [9].
• Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation [21].
• Primary androgen-independent prostate tumors but not benign prostate showed increased tyrosine-phosphorylated Ack1 and decreased Wwox [10].
• Molecular chaperone heat shock protein 90beta (Hsp90beta)-bound Ack1 and treatment of cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed tumorigenesis [10].

Regulatory relationships of TNK2

• Signaling through this complex is functionally relevant, because treatment with either p130(Cas) or Ack1 siRNA blocked Cdc42-induced migration [22].
• The interplay between Nedd4-2-related E3 ligases that regulate ACK1 levels and Cbl that modifies EGF receptor impinges on cell receptor dynamics [23].

Other interactions of TNK2

• Here we show the induction of tyrosine phosphorylation of ACK in response to temperature shift-down to 25 degrees C, and hypertonic shock, as well as stimulation with epidermal growth factor (EGF) in human embryonic kidney (HEK) 293 cells [14].
• A non-receptor tyrosine kinase ACK, which specifically binds to the GTP-bound form of Cdc42, was isolated as a putative target of Cdc42 [14].
• Therefore, the activation of ACK1 and subsequent downstream signaling require both Cdc42-dependent and Grb2-dependent processes within the cell [18].
• On the other hand, replacement of the corresponding region of TC10 with the AB region enabled TC10 to acquire ACK-binding ability [24].
• GEF activity of Ras-GRF1 toward Ha-Ras, as defined by in vitro GDP binding and release assays, was augmented after tyrosine phosphorylation by ACK1 [17].

Analytical, diagnostic and therapeutic context of TNK2

• PBL obtained by leukapheresis were subjected to NH4Cl (ACK) treatment to clear erythrocyte contamination; Ficoll separation was not performed [25].

References