Departments of Biochemistry and Molecular Genetics, Chicago, 60607, IL, USA.
Pathology, University of Illinois, Chicago, 60612, IL, USA.
Nat Commun. 2017 Nov 15;8(1):1508. doi: 10.1038/s41467-017-01574-5.
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. Conditional disruption of Pten in the mouse prostate leads to tumorigenesis and increased phosphorylation of PTK6 Y342, and disruption of Ptk6 impairs tumorigenesis. In human prostate tumor tissue microarrays, loss of PTEN correlates with increased PTK6 PY342 and poor outcome. These data suggest PTK6 activation promotes invasive prostate cancer induced by PTEN loss.
PTEN 的活性在前列腺癌中经常丧失。我们表明，酪氨酸激酶 PTK6（BRK）是 PTEN 的底物。PTK6 酪氨酸 342（PY342）的磷酸化促进激活，而酪氨酸 447（PY447）的磷酸化调节自动抑制。将 PTEN 引入 PTEN 缺失的前列腺癌细胞系中会导致 PY342 的去磷酸化，但不会导致 PY447 和 PTK6 的抑制。相反，PTEN 的敲低会促进 PTEN 阳性细胞中 PTK6 的激活。使用各种 PTEN 突变体构建体，我们表明 PTEN 的蛋白磷酸酶活性靶向 PTK6，其效率类似于直接使 PTK6 Y342 去磷酸化的磷酸酶 PTP1B。在小鼠前列腺中条件性敲除 Pten 会导致肿瘤发生和 PTK6 Y342 的磷酸化增加，而敲除 Ptk6 会损害肿瘤发生。在人类前列腺肿瘤组织微阵列中，PTEN 的缺失与 PTK6 PY342 的增加和不良预后相关。这些数据表明，PTK6 的激活促进了由 PTEN 缺失引起的侵袭性前列腺癌。
