Disrupting PTPRJ transmembrane-mediated oligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD.
Disrupting PTPRJ transmembrane-mediated oligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD.
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DOI：
10.3389/fonc.2022.1017947
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发表时间：
2022
影响因子：
4.7
通讯作者：
Mueller, Joerg P.
中科院分区：
文献类型：
--
作者：
Schwarz, Marie;Rizzo, Sophie;Paz, Walter Espinoza;Kresinsky, Anne;Thevenin, Damien;Mueller, Joerg P.
关键词：
受体蛋白酪氨酸磷酸酶（RPTP）PTPRJ（也称为DEP-1）已被鉴定为体外受体酪氨酸激酶FLT 3信号传导的负调节剂。在表达组成性活性的致癌受体酪氨酸激酶FLT 3 ITD的小鼠中，PTPRJ基因的失活加重了白血病发生的已知特征，揭示了PTPRJ的拮抗作用。导致组成性激酶活性和细胞转化的FLT 3 ITD突变经常发生在急性髓性白血病（AML）患者中。因此，PTPRJ的原位活化可用于消除致癌FLT 3信号传导。PTPRJ的活性受到同二聚化的抑制，而同二聚化是由跨膜结构域（TMD）相互作用介导的。TMD中的特异性甘氨酸至亮氨酸突变破坏寡聚化并抑制表皮生长因子受体（EGFR）和EGFR驱动的癌细胞表型。为了研究PTPRJ TMD突变蛋白对细胞系中FLT 3 ITD活性的影响，将内源性PTPRJ失活并由PTPRJ TMD突变体的稳定表达替代。与表达野生型的细胞相比，表达PTPRJ TMD突变体的AML细胞系中野生型和ITD突变的FLT 3的自磷酸化减少。这伴随着FLT 3介导的整体蛋白酪氨酸磷酸化和下游信号传导的减少。此外，PTPRJ TMD突变蛋白损害白血病细胞的增殖和体外转化。虽然PTPRJ的TMD突变蛋白表现出受损的自缔合，免疫沉淀蛋白的特异性磷酸酶活性保持不变。总之，本研究表明，PTPRJ TMD介导的自缔合的不稳定性增加了PTPRJ的原位活性，并损害AML细胞的FLT 3活性和FLT 3驱动的细胞表型。因此，原位破坏PTPRJ的寡聚化可以证明是限制白血病细胞中致癌FLT 3活性的有价值的治疗策略。
The receptor protein tyrosine phosphatase (RPTP) PTPRJ (also known as DEP-1) has been identified as a negative regulator of the receptor tyrosine kinase FLT3 signalling in vitro. The inactivation of the PTPRJ gene in mice expressing the constitutively active, oncogenic receptor tyrosine kinase FLT3 ITD aggravated known features of leukaemogenesis, revealing PTPRJ’s antagonistic role. FLT3 ITD mutations resulting in constitutively kinase activity and cell transformation frequently occur in patients with acute myeloid leukaemia (AML). Thus, in situ activation of PTPRJ could be used to abrogate oncogenic FLT3 signalling. The activity of PTPRJ is suppressed by homodimerization, which is mediated by transmembrane domain (TMD) interactions. Specific Glycine-to-Leucine mutations in the TMD disrupt oligomerization and inhibit the Epidermal Growth Factor Receptor (EGFR) and EGFR-driven cancer cell phenotypes. To study the effects of PTPRJ TMD mutant proteins on FLT3 ITD activity in cell lines, endogenous PTPRJ was inactivated and replaced by stable expression of PTPRJ TMD mutants. Autophosphorylation of wild-type and ITD-mutated FLT3 was diminished in AML cell lines expressing the PTPRJ TMD mutants compared to wild-type-expressing cells. This was accompanied by reduced FLT3-mediated global protein tyrosine phosphorylation and downstream signalling. Further, PTPRJ TMD mutant proteins impaired the proliferation and in vitro transformation of leukemic cells. Although PTPRJ’s TMD mutant proteins showed impaired self-association, the specific phosphatase activity of immunoprecipitated proteins remained unchanged. In conclusion, this study demonstrates that the destabilization of PTPRJ TMD–mediated self-association increases the activity of PTPRJ in situ and impairs FLT3 activity and FLT3-driven cell phenotypes of AML cells. Thus, disrupting the oligomerization of PTPRJ in situ could prove a valuable therapeutic strategy to restrict oncogenic FLT3 activity in leukemic cells.
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DOI：
10.3390/molecules23020395
发表时间：
2018-02-12
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Hendriks W;Bourgonje A;Leenders W;Pulido R
通讯作者：
Pulido R
影响因子：
4
作者：
Gerhart J;Thévenin AF;Bloch E;King KE;Thévenin D
通讯作者：
Thévenin D
影响因子：
64.8
作者：
Bilwes, AM;denHertog, J;Noel, JP
通讯作者：
Noel, JP
影响因子：
4.8
作者：
Bloch, Elizabeth;Sikorski, Eden L.;Thevenin, Damien
通讯作者：
Thevenin, Damien
影响因子：
3.7
作者：
Bohmer, Sylvia-Annette;Weibrecht, Irene;Bohmer, Frank-D.
通讯作者：
Bohmer, Frank-D.