A phosphotyrosine switch regulates organic cation transporters

Sprowl, Jason A.; Ong, Su Sien; Gibson, Alice A.; Hu, Shuiying; Du, Guoqing; Lin, Wenwei; Li, Lie; Bharill, Shashank; Ness, Rachel A.; Stecula, Adrian; Offer, Steven M.; Diasio, Robert B.; Nies, Anne T.; Schwab, Matthias; Cavaletti, Guido; Schlatter, Eberhard; Ciarimboli, Giuliano; Schellens, Jan H.M.; Isacoff, Ehud Y.; Šali, Andrej; Chen, Taosheng; Baker, Sharyn D.; Sparreboom, Alex; Pabla, Navjotsingh

doi:10.1038/ncomms10880

Cited by 110 publications

(109 citation statements)

References 69 publications

(113 reference statements)

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“…S4). Because many of these transporters are also regulated by tyrosine phosphorylation (49,50), and because their malfunction can contribute to human disease, it will be important in the future to determine whether their structures contain a functional SH2-like motif similar to that discovered here and whether their mechanism of regulation resembles that depicted in Fig. 4E.…”

Section: Discussionmentioning

confidence: 78%

“…With the evidence for a functional SH2-like motif in the membrane-spanning domain of band 3 now established, and with considerable data showing that many other membrane-spanning solute transporters are also regulated by tyrosine kinases (49,50), the question naturally arose of whether other membrane-spanning proteins might have evolved a similar functional SH2 signature sequence to enable their regulation by tyrosine kinases. Examination of the literature reveals that sequences similar to GSFLVR can indeed be found in numerous transport proteins, ranging from neurotransmitter symporters to glucose transporters to cation-Cl − electroneutral cotransporters, etc.…”

Section: Discussionmentioning

confidence: 99%

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Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

Puchulu-Campanella

Turrini

2016

Proc. Natl. Acad. Sci. U.S.A.

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Src homology 2 (SH2) domains are composed of weakly conserved sequences of ∼100 aa that bind phosphotyrosines in signaling proteins and thereby mediate intra-and intermolecular protein-protein interactions. In exploring the mechanism whereby tyrosine phosphorylation of the erythrocyte anion transporter, band 3, triggers membrane destabilization, vesiculation, and fragmentation, we discovered a SH2 signature motif positioned between membrane-spanning helices 4 and 5. Evidence that this exposed cytoplasmic sequence contributes to a functional SH2-like domain is provided by observations that: (i) it contains the most conserved sequence of SH2 domains, GSFLVR; (ii) it binds the tyrosine phosphorylated cytoplasmic domain of band 3 (cdb3-PO 4 ) with K d = 14 nM; (iii) binding of cdb3-PO 4 to erythrocyte membranes is inhibited both by antibodies against the SH2 signature sequence and dephosphorylation of cdb3-PO 4 ; (iv) label transfer experiments demonstrate the covalent transfer of photoactivatable biotin from isolated cdb3-PO 4 (but not cdb3) to band 3 in erythrocyte membranes; and (v) phosphorylation-induced binding of cdb3-PO 4 to the membrane-spanning domain of band 3 in intact cells causes global changes in membrane properties, including (i) displacement of a glycolytic enzyme complex from the membrane, (ii) inhibition of anion transport, and (iii) rupture of the band 3-ankyrin bridge connecting the spectrin-based cytoskeleton to the membrane. Because SH2-like motifs are not retrieved by normal homology searches for SH2 domains, but can be found in many tyrosine kinase-regulated transport proteins using modified search programs, we suggest that related cases of membrane transport proteins containing similar motifs are widespread in nature where they participate in regulation of cell properties.SH2 domain motif | tyrosine phosphorylation | erythrocyte glycolysis | anion exchanger 1 | regulation of transport proteins P rotein tyrosine phosphorylation is involved in the regulation of most cellular process, including proliferation, survival, differentiation, responses to stress, and control of cell shape/motility (1). Whereas phosphotyrosine binding (PTB) domains may mediate association with tyrosine-containing sequences regardless of their phosphorylation state, Src homology 2 (SH2) domains promote protein association only when critical tyrosine residues become phosphorylated. This strict dependence on tyrosine phosphorylation creates a molecular switch that can be sensitively controlled by upstream tyrosine kinases (1). Whereas some SH2 domains facilitate association between heterologous proteins in a signaling pathway, others mediate intrapolypeptide interactions that change protein conformation and thereby alter signaling function (2). In all cases, association between the SH2 domain and the interacting phosphotyrosine involves formation of weak interactions between a highly conserved G(S/T)FLVR sequence of the SH2 domain and the phosphate present on the phosphorylated tyrosine. To date, all 120 known SH2 domain...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

Puchulu-Campanella

Turrini

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Alternatively, tyrosine kinase inhibitors reduced OCT2 activity and oxaliplatininduced acute neuropathy in vivo, suggesting a role for tyrosine phosphorylation in regulation of OCT2. (Sprowl et al, 2016). It is important to note that reduction in cisplatin sensitivity and accumulation was most pronounced for ciPTEC-OAT3, whereas ASP + accumulation was reduced mostly in ciPTEC-OAT1.…”

Section: Discussionmentioning

confidence: 95%

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

et al. 2018

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Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC 50 34 6 1 mM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC 50 45 6 6 and 64 6 11 mM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by V max of the OCT2-model substrate ASP + (23.5 6 0.1, 13.1 6 0.3, and 21.6 6 0.6 minutes 21 in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 6 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 6 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters.

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“…For example, in mice, genetic deletion of SARM1 blocks the development of vincristine‐induced peripheral polyneuropathy and efforts are under way to develop SARM‐1 inhibitors for clinical use . Another pathway being explored is the genetic or pharmacological knockout of transporters localized to the DRG in mice, such as OATP1B2 (OATP1B1 in humans), organic cation transporter novel type (OCTN2) and OCT2, protects against CIPN associated with vincristine, as well as other chemotherapeutic class such as taxanes and platinums . Transporter inhibitors such as nilotinib and dasatinib are currently entering early stage clinical trial for prevention of CIPN.…”

Section: Treatment Optionsmentioning

confidence: 99%

Vinca alkaloids, thalidomide and eribulin‐induced peripheral neurotoxicity: From pathogenesis to treatment

Islam

Lustberg

Staff

et al. 2019

J Peripheral Nervous Sys

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Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin. K E Y W O R D S assessment, eribulin, peripheral neurotoxicity, thalidomide, vinca alkaloids

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A phosphotyrosine switch regulates organic cation transporters

Cited by 110 publications

References 69 publications

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

Vinca alkaloids, thalidomide and eribulin‐induced peripheral neurotoxicity: From pathogenesis to treatment

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