Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Virobay, Menlo Park, CA 94025, USA.
Genes Cells. 2010 Jun;15(7):711-724. doi: 10.1111/j.1365-2443.2010.01410.x. Epub 2010 Jun 7.
Two isoforms of the transmembrane protein tyrosine phosphatase PTPalpha, which differ by nine amino acids in their extracellular regions, are expressed in a tissue-specific manner. Over-expression of the shorter isoform transforms rodent cells, and it has previously been reasonable to assume that this was a direct consequence of its dephosphorylation and activation of Src. Transformation by the longer wild-type isoform has not previously been studied. We tested the activities of both isoforms in NIH3T3 cells and found that, while both dephosphorylated and activated Src similarly, only the shorter isoform induced focus formation or anchorage-independent growth. Differences in phosphorylation of PTPalpha at its known regulatory sites, Grb2 binding to PTPalpha, phosphorylation level of focal adhesion kinase by PTPalpha, or overall localization were excluded as possible explanations for the differences in transforming activities. The results suggest that transformation by PTPalpha involves at least one function other than, or in addition to, its activation of Src and that this depends on PTPalpha's extracellular domain. Previous studies have suggested that PTPalpha might be a useful target in breast and colon cancer therapy, and the results presented here suggest that it may be advantageous to develop isoform-specific therapeutic reagents.
两种跨膜蛋白酪氨酸磷酸酶 PTPalpha 的同工型，它们在细胞外区域的九个氨基酸不同，以组织特异性的方式表达。较短同工型的过表达可转化啮齿动物细胞，以前认为这是其去磷酸化和激活Src 的直接后果。以前尚未研究过长型野生型同工型的转化。我们在 NIH3T3 细胞中测试了两种同工型的活性，发现虽然两者都能去磷酸化和激活Src，但只有较短的同工型诱导焦点形成或锚定非依赖性生长。已排除 PTPalpha 在其已知调节位点的磷酸化、Grb2 与 PTPalpha 的结合、PTPalpha 对粘着斑激酶的磷酸化水平或整体定位等方面的差异作为转化活性差异的可能解释。结果表明，PTPalpha 的转化作用至少涉及其激活Src 以外的一种功能，并且这种功能依赖于 PTPalpha 的细胞外结构域。以前的研究表明 PTPalpha 可能是乳腺癌和结肠癌治疗的一个有用靶点，这里提出的结果表明，开发同工型特异性治疗试剂可能是有利的。
