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PubMed1989

Peptide sequencing and site-directed mutagenesis identify tyrosine-319 as the active site tyrosine of Escherichia coli DNA topoisomerase I.

Tyrosine 319 of E. coli topoisomerase I is shown to be the active site tyrosine that becomes covalently attached to a DNA 5' phosphoryl group during the transient breakage of a DNA internucleotide bond by the enzyme. The tyrosine was mapped by trapping the covalent complex between the DNA and DNA topoisomerase I, digesting the complex exhaustively with trypsin, and sequencing the DNA-linked tryptic peptide. Site-directed mutagenesis converting Tyr-319 to a serine or phenylalanine completely inactivates the enzyme. The structure of the enzyme and its catalysis of DNA strand breakage, passage, and rejoining are discussed in terms of the available information.

Amino Acid Sequence↗
PubMed1996

G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor.

Insulin-like growth factor I is an autocrine/paracrine factor for vascular smooth muscle cells and is required for angiotensin II- and thrombin-induced mitogenesis. The insulin-like growth factor I-triggered signaling pathway involves autophosphorylation of the beta-subunit of its tyrosine kinase receptor and phosphorylation of insulin receptor substrate-1, the latter providing binding sites for proteins with src homology-2 domains. In rat aortic smooth muscle cells we observed that both angiotensin II and thrombin induced rapid tyrosine phosphorylation of insulin receptor substrate-1. Our results also demonstrated that these mitogens rapidly stimulated phosphorylation of the insulin-like growth factor 1 receptor beta-chain. These data demonstrate a novel interaction between the G-protein coupled angiotensin II and thrombin receptors and the tyrosine-kinase insulin-like growth factor I receptor.

Angiotensin II↗
PubMed1998

Multiple phosphorylation of chicken protein tyrosine phosphatase 1 and human protein tyrosine phosphatase 1B by casein kinase II and p60c-src in vitro.

We have cloned a soluble chicken protein tyrosine phosphatase, named CPTP1, from the cDNA library of chicken intestine. The CPTP1 showed 92% sequence identity to the corresponding 321 amino acid residues of human PTP1B (HPTP1B). CPTP1 lacked 13 amino acids of the N-terminal region compared with HPTP1B, while the C-terminal 48 amino acid sequence of this protein was distinct from those of other PTPs. In vitro phosphorylation and phosphoamino acid analysis showed that both CPTP1 and HPTP1B were phosphorylated on serine and threonine residues near their N-terminus by casein kinase II (CKII). Furthermore, phosphorylation of CPTP1 by CKII resulted in an inhibition of its phosphatase activity in vitro. Interestingly, both CPTP1 and HPTP1B were also tyrosine-phosphorylated near their N-terminus by p60c-src. When we examined the vanadate effect, in the absence of vanadate, the tyrosine-phosphorylated CPTP1 by p60c-src was autodephosphorylated by its own phosphatase activity. These results suggest that both CPTP1 and HPTP1B might play an important role in CKII- and p60c-src-induced signal transduction cascades.

Amino Acid Sequence↗
PubMed1996

Effects of 3-iodo-L-tyrosine, a tyrosine hydroxylase inhibitor, on eye pigmentation and biogenic amines in the planarian, Dugesia dorotocephala.

Planarians (Dugesia dorotocephala) were evaluated as bioassay organisms to detect inhibition of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. Thirty planaria per dose were exposed to 0 (control), 0.001, 0.01, 0.1, or 1 mM 3-iodo-L-tyrosine (monoiodotyrosine or MIT) in standard test media beginning 24 hr before decapitation and continuing for 13 days. Complete regeneration of normal heads occurred over the first 6 days in all dose groups, a response reported to be partially dependent on catecholamines. Beginning on Day 7, the black eye pigments began fading in the 0.1 and 1 mM dose groups and were completely absent macroscopically and histologically by Day 11. The 0, 0.001, and 0.01 mM dose groups did not lose visible eye pigments. On Day 13, 3 planaria/dose were harvested for histopathology; 15 planaria/dose were decapitated a second time and remained in MIT solutions; and 12 planaria/dose were left intact, placed in fresh control media, and evaluated for eye repigmentation. Normal head regeneration (including eyes) was detected grossly in all groups, even in those animals devoid of eye pigments at the time of decapitation. As before, eye pigments began fading 7 days after decapitation (Day 20 of experiment) and were completely absent in 73 and 33% of the animals in the 0.1 and 1 mM groups, respectively, on Day 25. All animals moved to control media reformed eye pigments, beginning within 48 hr. Analysis of the decapitated heads by HPLC-ECD on Day 13 revealed a significant decrease in dopamine and 5-hydroxytryptamine (serotonin) concentrations in MIT-exposed animals. Tyrosine hydroxylase activity (and possibly tyrosinase activity) was shown to be inhibited by the highest two concentrations for whole planaria homogenates in vitro.

Animals↗
PubMed1985

Catecholamine neurons with Alzheimer's neurofibrillary changes and alteration of tyrosine hydroxylase. Immunohistochemical investigation of tyrosine hydroxylase.

Immunohistochemistry with antisera against tyrosine hydroxylase was performed on neurons with Alzheimer's neurofibrillary changes in the substantia nigra and locus ceruleus. These specimens were obtained from brains with Alzheimer's disease, Pick's disease, progressive supranuclear palsy, Alzheimer's type parkinsonism, parkinsonism-dementia complex on Guam, and normal aging. Under these neurologic conditions the affected catecholamine neurons with Alzheimer's neurofibrillary changes were stained positively with antisera against tyrosine hydroxylase. The results suggested that in these neurons, Alzheimer's neurofibrillary changes seemed to develop independently before the reduction of tyrosine hydroxylase protein synthesis.

Adult↗
PubMed2003

Could the tyrosine-histidine ligand to CuB in cytochrome c oxidase be coordinatively labile? Implications from a quantum chemical model study of histidine substitutional lability and the effects of the covalent tyrosine-histidine cross-link.

Density functional theory calculations have been used to evaluate the effects of inter-ring interactions within a covalently linked histidine-tyrosine cofactor such as that which is a ligand to the Cu(B) centre in cytochrome c oxidases and to investigate the energetics of histidine substitution at the Cu(B) centre. Small, but significant, perturbations of the redox potentials and/or p K(a) values of the histidine imidazole, the tyrosine phenol and the copper ion are found. The Cu(B)-N(cofactor) bond is estimated to be weaker than the Cu(B)-N(histidine coligand) bonds in the Cu(B)(I) state and in the Cu(B) (II) state when the cofactor is oxidized, by approximately 13 kJ/mol and approximately 23 kJ/mol, respectively. The calculations reveal that displacement of a histidine ligand from the Cu(B) centre, as is suggested in proposals of "histidine cycle" mechanisms for proton pumping in cytochrome c oxidases, is only energetically feasible if accompanied by protonation of the histidine imidazole and coupled to an endothermic process. It is proposed that the histidine-tyrosine cofactor ought to be considered as the substitutionally labile ligand to Cu(B) as the covalent crosslink would ensure displacement of the cofactor from Cu(B)-driven helix deformation. It is estimated that this process could store up to approximately 70 kJ/mol, which, based upon thermodynamic considerations, is sufficient for the pumping of two protons in the later steps (reductive phase) of the catalytic cycle. Ramifications of this proposition for the mechanism of proton pumping in cytochrome c oxidases are discussed.

Amino Acid Substitution↗
PubMed1994

Tyrosine-rich acidic matrix protein (TRAMP) is a tyrosine-sulphated and widely distributed protein of the extracellular matrix.

Tyrosine-rich acidic matrix protein (TRAMP; 22 kDa extracellular matrix protein; dermatopontin) is a protein that co-purifies with lysyl oxidase and with dermatan sulphate proteoglycans, with possible functions in cell-matrix interactions and matrix assembly. Using a rabbit polyclonal antiserum raised against porcine TRAMP, which cross-reacts with both the human and murine forms of the protein, we show by immunoblotting that TRAMP has a widespread tissue distribution, including skin, skeletal muscle, heart, lung, kidney, cartilage and bone. In cultures of human skin fibroblasts, TRAMP incorporates both [35S]sulphate and [3H]tyrosine and is secreted into the medium, as shown by immunoprecipitation. Amino acid analysis of immunoprecipitated TRAMP demonstrates that many of the tyrosine residues in TRAMP are sulphated.

Animals↗
PubMed1995

Homodimerization and intermolecular tyrosine phosphorylation of the Tyk-2 tyrosine kinase.

The Jak kinases and Stat transcription factors play a major role in signaling of various cytokines including IFN alpha. In this report we show a ligand-independent interaction between Tyk-2 and Jak-1 kinases. We also demonstrate that the Tyk-2 kinase forms a homodimer that has the ability to undergo intermolecular tyrosine phosphorylation. The formation of the Tyk-2 homodimer is independent of both tyrosine phosphorylation and the presence of the tyrosine kinase domain.

Cell Line↗
PubMed1988

Soluble tyrosine hydroxylase (tyrosine 3-monooxygenase) from bovine adrenal medulla: large-scale purification and physicochemical properties.

A new procedure that permits large-scale purification of tyrosine 3-monooxygenase (tyrosine hydroxylase) (L-tyrosine,tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2) from the cytosolic fraction of bovine adrenal medulla is described. The homogenous enzyme revealed a subunit Mr of 60,000 and a specific activity of 425 nmol.min-1.mg-1. The N-terminal amino-acid sequence (27 residues) revealed 89% homology with the human pheochromocytoma enzyme as deduced from its cDNA sequence. The pure enzyme contained 0.66 +/- 0.09 mol iron, 0.13 mol zinc and 0.62 +/- 0.04 mol phosphate per mol subunit of Mr = 60,000. A broad light absorption band with its maximum around 700 nm (epsilon 700 nm = 1.3 (mM monomer)-1.cm-1) explains its blue-green color. EPR spectra at 3.6 K revealed high-spin Fe(III) (S = 5/2) in an environment of nearly axial symmetry (g values at 7.2-6.7, 4.7-5.3 and 1.9-2.0). A close correlation was observed between the absorbance at 700 nm and the intensity of the axial type of EPR spectrum. The absorption peak at 700 nm is compatible with a ligand-to-iron charge-transfer transition as a result of catecholate coordination to the iron. Physicochemical studies suggest that the enzyme does not undergo such major substrate- or cofactor-induced conformational changes as have been reported for the related enzyme, phenylalanine hydroxylase.

Adrenal Medulla↗
PubMed1995

Purification of a major tyrosine kinase from RBL-2H3 cells phosphorylating Fc epsilon RI gamma-cytoplasmic domain and identification as the Btk tyrosine kinase.

Immunoglobulin E high affinity receptor-mediated signal transduction in mast cells results in a number of protein tyrosine kinases being activated as very early events in the process leading to degranulation. Some of these, such as the src kinases and the syk kinase, are known to be involved in this receptor-associated activation. In this paper we describe the search for other activation-associated tyrosine kinases by the ability to phosphorylate a cytoplasmic domain peptide of the Fc epsilon RI gamma-subunit. In utilizing a purification step previously used to isolate the 72 kDa syk kinase, we detected another kinase of molecular weight 79 kDa which we designated cd gamma kinase. The kinase was purified to near homogeneity by Heparin-agarose, Mono Q, and CM Sepharose chromatographies. The yield of enzyme was approx. 200 micrograms/10(9) cells. We characterized this kinase by its ability to phosphorylate both the cd gamma peptide (Km = 0.2 mM) and the cytoplasmic fragment of the Band III protein. The cd gamma kinase was distinguished from syk by inability to be precipitated by anti-syk antiserum and by partial peptide mapping. Cd gamma kinase was also distinguished from syk by cd gamma peptide and Band III substrate specificity. We identified the cd gamma kinase by Western blotting and by partial phosphopeptide mapping as Btk, the B-cell tyrosine kinase found to be defective in X-linked agammaglobulinemia.

Amino Acid Sequence↗
PubMed1998

Inhibition of FGF-1 receptor tyrosine kinase activity by PD 161570, a new protein-tyrosine kinase inhibitor.

Through direct synthetic efforts we discovered a small molecule which is a 40 nanomolar inhibitor of the human FGF-1 receptor tyrosine kinase. 1-Tert-butyl-3-[6-(2,6-dichloro-phenyl)-2-(4-diethylamino-butylamino)-py rido[2,3-d]pyrimidin-7-yl]-urea (PD 161570) had about 5- and 100-fold greater selectivity toward the FGF-1 receptor (IC50 = 40 nM) compared with the PDGFbeta receptor (IC50 = 262 nM) or EGF receptor (IC50 = 3.7 microM) tyrosine kinases, respectively. In addition, PD 161570 suppressed constitutive phosphorylation of the FGF-1 receptor in both human ovarian carcinoma cells (A121(p)) and Sf9 insect cells overexpressing the human FGF-1 receptor and blocked the growth of A121(p) cells in culture. The results demonstrate a novel synthetic inhibitor with nanomolar potency and specificity towards the FGF-1 receptor tyrosine kinase.

Animals↗
PubMed1985

Effects of tyrosine-26 and tyrosine-64 nitration on the photoreactions of bacteriorhodopsin.

In the dark, all titratable tyrosine residues of bacteriorhodopsin have pK's of greater than 11.0, which may be caused by the hydrophobic environment for buried residues and by high negative charge density for surface residues [Scherrer, P., & Stoeckenius, W. (1984) Biochemistry 23, 6195-6202]. Under illumination, deprotonation of only one tyrosine is observed in the micro- and millisecond time ranges of the photocycle; this is Tyr-64. Nitration of Tyr-64 decreases the chromophore absorbance, shifts the absorption maximum to 535 nm, and affects photocycle kinetics. However, restoring its native pK by reduction after nitration has no effect on the changes in photocycle kinetics or absorbance of the chromophore. Nitration of Tyr-64 apparently causes a conformational change in bR, which is independent of the pK of its phenolic group. These observations contradict earlier conclusions that in the photocycle a tyrosine residue directly interacts with the Schiff base during its deprotonation or reprotonation. The protonation state of Tyr-26 and the alkaline chromophore transition are correlated, as shown earlier (Scherrer & Stoeckenius, 1984). Lowering the pK of Tyr-26 by nitration decreases the M-decay rate, and this effect is partially reversed by reduction of the nitro group. We conclude that Tyr-26 may be located close to the chromophore and interact with it; but its protonation state does not change at physiological pH and in the microsecond time range of the photocycle. Tyr-64 is apparently located at or close to the external surface; its modification strongly affects the chromophore but apparently indirectly and not through its protonation changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Tyrosine kinase inhibitors. 4. Structure-activity relationships among N- and 3-substituted 2,2'-dithiobis(1H-indoles) for in vitro inhibition of receptor and nonreceptor protein tyrosine kinases.

A series of 3-substituted 2,2'-dithiobis(1H-indoles) were synthesized and evaluated for their ability to inhibit the tyrosine kinase activity of both the epidermal growth factor receptor (EGFR) and the nonreceptor pp60v-src tyrosine kinase, to extend the available structure-activity relationships for this series. The majority of the compounds were prepared either by reaction of 2-chloro-1-methylindole-3-carbonyl chloride with amines, followed by thiomethylation, demethylation, and oxidative dimerization, or by reaction of isocyanates with the anion of 1-methyl-2-indolinethione followed by dimerization. Overall, inhibitory activity is retained by analogues having a wide variety of side chains. A series of 3-carboxamide analogues had moderate to good activity against isolated EGFR (IC50s 1-20 microM), with monoalkyl substitution of the carboxamide being optimal. Polar side chains were generally less effective than lipophilic ones, with benzyl being particularly effective. However, N,N-disubstitution was the most effective pattern for inhibition of pp60v-src. A variety of substituted N-phenylcarboxamides had lower activity against EGFR than the parent derivative, and a N-thienylcarboxamide also had low activity. A series of 3-ketones, including methyl, phenyl, and furyl derivatives, showed moderate activity against the pp60v-src kinase, but were less effective against EGFR. The mechanism of inhibition of both kinases by these drugs was shown to be noncompetitive with respect to both ATP and peptide substrate. Selected compounds inhibited the growth of Swiss 3T3 cells with IC50s in the low micromolar range and inhibited bFGF-mediated intracellular tyrosine phosphorylation in the same cell line. Thiol inhibits the effects of the compounds, suggesting that one possible mechanism of inhibition is thiol-disulfide exchange with thiol-containing residues in the catalytic sites. Crystal structures of two representative compounds show a folded, V-shaped structure, with the disulfide bridge exposed, consistent with this hypothesis.

3T3 Cells↗
PubMed1994

Tyrosine kinase inhibitors. 3. Structure-activity relationships for inhibition of protein tyrosine kinases by nuclear-substituted derivatives of 2,2'-dithiobis(1-methyl-N-phenyl-1H-indole-3-carboxamide).

A series of indole-substituted 2,2'-dithiobis(1-methyl-N-phenyl-1H-indole-3-carboxamides) were prepared and evaluated for their ability to inhibit the tyrosine kinase activity of both the epidermal growth factor receptor (EGFR) and the nonreceptor pp60v-src tyrosine kinase. The compounds were synthesized by conversion of appropriate 1-methyloxindoles to 1-methyl-2-indolinethiones with P2S5 followed by subsequent reaction with NaH and phenyl isocyanate and oxidative dimerization of the resulting 2,3-dihydro-N-phenyl-2-thioxo-1H-indole-3-carboxamides. The parent compound and many of the substituted analogues were moderately potent inhibitors of both kinase enzymes, but no clear relationships were seen between substitution on the indole ring and inhibitory activity. While 4-substituted compounds were generally inactive, 5-substituted derivatives with electron-withdrawing groups showed inhibitory activity. However, none of the substituted compounds showed significantly better activity than the unsubstituted parent compound. There was generally a good correlation between activity against the EGFR and pp60v-src kinases, but several compounds did show some specificity (> 20-fold) of inhibition; 5-Cl and 5-Br derivatives preferentially inhibited pp60v-src, while the 5-CF3 compound preferentially inhibited EGFR. Selected compounds from the series were found to inhibit the growth of Swiss 3T3 fibroblasts with IC50S in the range 2-25 microM, the most active being 4-substituted derivatives. The compounds inhibited bFGF-mediated protein tyrosine phosphorylation in intact cells more effectively than EGFR- or PDGF-mediated phosphorylation.

3T3 Cells↗
PubMed1993

Identification of a putative tyrosine-O-sulphate (TyrS) receptor possibly functioning in the biosynthetic transport of tyrosine-sulphated proteins in Madin-Darby canine kidney cells.

By employing an affinity-gel fractionation technique coupled to Western-blot analysis, we have identified a 175 kDa tyrosine-O-sulphate (TyrS)-binding protein present in Madin-Darby canine kidney (MDCK) cells. The binding of this TyrS-binding protein to TyrS covalently bonded to Sepharose gel was found to be pH-dependent, being strong from pH 8.0 down to pH 6.5 and increasingly weak at pH 6.0 and below. Results obtained from Triton X-114 temperature-induced phase separation and sodium carbonate buffer (pH 11) extraction experiments indicated that the TyrS-binding protein is an integral membrane protein. This 175 kDa TyrS-binding protein was found to be present in association with a major tyrosine-sulphated protein, the apically secreted 80 kDa glycoprotein (gp 80), in cell lysate prepared from MDCK cells maintained under normal growth conditions. When the cell lysate used was prepared from MDCK cells pretreated with 20 mM sodium chlorate, a metabolic sulphation inhibitor, the complex formed between the two proteins could no longer be detected, indicating that the binding of the TyrS-binding protein is through the TyrS residue(s) of gp 80. Both cell-surface biotinylation and cell-surface trypsinization studies demonstrated the predominantly, if not exclusively, intracellular location of the TyrS-binding protein. Furthermore, radioactive pulse-chase experiments revealed that the newly synthesized radiolabelled fibronectin and gp 80 were present in complexes with the TyrS-binding protein in MDCK cells pulse-labelled with [35S]methionine or [35S]sulphate. Exogenous [35S]methionine-labelled gp 80 added to the medium, on the other hand, was not found to be present in association with the TyrS-binding protein in MDCK cells over a 2-h time course. These results strongly suggested the identity of the 175 kDa TyrS-binding protein as a putative 'TyrS receptor', possibly functioning in the biosynthetic transport of tyrosine-sulphated proteins in MDCK cells.

Animals↗
PubMed1989

Peptide sequencing and site-directed mutagenesis identify tyrosine-727 as the active site tyrosine of Saccharomyces cerevisiae DNA topoisomerase I.

Extensive digestion of the covalent intermediate between DNA and Saccharomyces cerevisiae DNA topoisomerase I with trypsin yields a 7-amino acid peptide covalently linked to DNA. Direct sequencing of the DNA-linked peptide identifies Tyr-727 as the active site tyrosine that forms an O4-phosphotyrosine bond with DNA when the enzyme cleaves a DNA phosphodiester bond. Site-directed mutagenesis of the cloned yeast TOP1 gene encoding the enzyme confirms the essentiality of Tyr-727 for the relaxation of supercoiled DNA by the enzyme. From amino acid sequence homology, Tyr-771 and -773 are readily identified as the active site tyrosines of Schizosaccharomyces pombe and human DNA topoisomerase I, respectively. Sequence comparison and site-directed mutagenesis also implicate Tyr-274 of vaccinia virus DNA topoisomerase as the active site residue. There appears to be a 70-amino acid domain near the carboxyl terminus of eukaryotic DNA topoisomerase I and vaccinia topoisomerase, within which the active site tyrosine resides.

Amino Acid Sequence↗
PubMed1995

Staphylococcal enterotoxins modulate interleukin 2 receptor expression and ligand-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription (Stat proteins).

Staphylococcal enterotoxins (SE) stimulate T cells expressing the appropriate variable region beta chain of (V beta) T-cell receptors and have been implicated in the pathogenesis of several autoimmune diseases. Depending on costimulatory signals, SE induce either proliferation or anergy in T cells. In addition, SE can induce an interleukin-2 (IL-2) nonresponsive state and apoptosis. Here, we show that SE induce dynamic changes in the expression of and signal transduction through the IL-2 receptor (IL-2R) beta and gamma chains (IL-2R beta and IL-2R gamma) in human antigen-specific CD4+ T-cell lines. Thus, after 4 hr of exposure to SEA and SEB, the expression of IL-2R beta was down-regulated, IL-2R gamma was slightly up-regulated, while IL-2R alpha remained largely unaffected. The changes in the composition of IL-2Rs were accompanied by inhibition of IL-2-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription called Stat3 and Stat5. In parallel experiments, IL-2-driven proliferation was inhibited significantly. After 16 hr of exposure to SE, the expression of IL-2R beta remained low, while that of IL2R alpha and IL2R gamma was further up-regulated, and ligand-induced tyrosine phosphorylation of Jak3 and Stat proteins was partly normalized. Yet, IL-2-driven proliferation remained profoundly inhibited, suggesting that signaling events other than Jak3/Stat activation had also been changed following SE stimulation. In conclusion, our data suggest that SE can modulate IL-2R expression and signal transduction involving the Jak/Stat pathway in CD4+ T-cell lines.

Apoptosis↗
PubMed1996

Specific association of tyrosine-phosphorylated c-Cbl with Fyn tyrosine kinase in T cells.

Fyn is a Src family protein-tyrosine kinase functionally associated with the T-cell antigen receptor (TcR)/CD3 receptor complex. We have demonstrated earlier that the TcR/CD3-induced activation of Fyn results in tyrosine phosphorylation of several Fyn-associated proteins, including a protein of 116 kDa. In this report, we identify the Fyn-associated 116-kDa phosphoprotein (p116) as c-Cbl. The identity of p116 has been demonstrated by its specific reactivity with anti-Cbl and similarity of phosphopeptides generated by V8 proteolysis of phospho-Cbl and p116. We demonstrate here that the association of Fyn and c-Cbl is direct and does not require the presence of other proteins. We also demonstrate that Fyn is the Src family kinase that preferentially interacts with c-Cbl in T cells. The fraction of c-Cbl capable of coprecipitating with Fyn is increased by TcR/CD3 ligation. This increase is likely due to the involvement of Fyn SH2 in the interactions between Fyn and tyrosine-phosphorylated c-Cbl.

Clone Cells↗