降低或增加酪氨酸磷酸酶 SHP2（由 PTPN11 编码）活性的突变会通过改变磷酸酶活性而促进发育障碍和多种恶性肿瘤。我们发现 SHP2 是一类独特的表观遗传酶；被激酶 ACK1/TNK2 磷酸化后，pSHP2 被雄激素受体 (AR) 护送至染色质，擦除迄今为止未识别的 pY54-H3（组蛋白 H3 在 Tyr54 处的磷酸化）表观遗传标记，从而触发 AR 的转录程序。多发性雀斑努南综合征 (NSML) 患者、SHP2 敲入小鼠和 ACK1 敲除小鼠的 pY54-H3 显着增加，导致 AR 转录组丢失。相比之下，具有高 pSHP2 和 pACK1 活性的前列腺肿瘤表现出 pY54-H3 水平进行性下调以及与疾病严重程度相关的较高 AR 表达。总体而言，pSHP2/pY54-H3 信号传导充当 AR 稳态的哨兵，不仅解释了 NSML 患者的生长迟缓、生殖器异常和不孕，还解释了前列腺癌患者中 AR 的显着上调。© 2024。作者。

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.© 2024. The Author(s).