PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.
PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization.
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DOI：
10.1038/onc.2010.543
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发表时间：
2011-04-07
期刊：
影响因子：
8
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Zhi HY;Hou SW;Li RS;Basir Z;Xiang Q;Szabo A;Chen G
酪氨酸磷酸化受蛋白酪氨酸激酶（PTKs）和蛋白酪氨酸磷酸酶（PTPs）的严格调控，在恶性转化和进展中起关键作用。虽然PTKs在调节乳腺癌生长中的作用已经确立，但PTPs的作用仍不清楚。在这里，我们报道酪氨酸磷酸酶PTPH1通过调节维生素D受体（VDR）的表达刺激乳腺癌的生长。PTPH1在49%的原发性乳腺癌中过表达，其蛋白表达水平与临床转移呈正相关，提示其致癌活性。事实上，PTPH1通过一种独立于其磷酸酶活性的机制促进乳腺癌的生长，但依赖于其对核受体VDR蛋白表达的刺激作用，而耗尽诱导的VDR可消除PTPH1的致癌活性。进一步的分析表明，PTPH1结合VDR并增加其细胞质积累，导致它们相互稳定和稳定表达。核定位缺陷的VDR消除了独立于1,25 -二羟基维生素D3（维生素D3）的受体的生长抑制活性。这些结果揭示了一种新的模式，蛋白质酪氨酸磷酸酶可能通过增加核受体的细胞质易位来刺激乳腺癌的生长，从而导致它们的相互稳定。
Tyrosine phosphorylation is tightly regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), and plays a critical role in malignant transformation and progression. While PTKs have a well-established role in regulating breast cancer growth, contribution of PTPs remains mostly unknown. Here, we report that the tyrosine phosphatase PTPH1 stimulates breast cancer growth through regulating vitamin D receptor (VDR) expression. PTPH1 was shown to be over-expressed in 49% of primary breast cancer and levels of its protein expression positively correlate with the clinic metastasis, suggesting its oncogenic activity. Indeed, PTPH1 promotes breast cancer growth by a mechanism independent of its phosphatase activity but dependent of its stimulatory effect on the nuclear receptor VDR protein expression and depletion of induced VDR abolishes the PTPH1 oncogenic activity. Additional analyses showed that PTPH1 binds VDR and increases its cytoplasmic accumulation leading to their mutual stabilization and stable expression of a nuclear localization deficient VDR abolishes the growth-inhibitory activity of the receptor independent of 1, 25-dihydroxyvitamin D3 (vitamin D3). These results reveal a new paradigm in which a protein tyrosine phosphatase may stimulate breast cancer growth through increasing cytoplasmic translocation of a nuclear receptor leading to their mutual stabilization.