Weng L P, Yuan J, Yu Q
Pulmonary Center Department of Medicine Department of Biochemistry Boston University Medical Center Boston, Massachusetts 02118, USA.
Curr Biol. 1998 Feb 26;8(5):247-56. doi: 10.1016/s0960-9822(98)70106-x.
The protein tyrosine phosphatase family comprises transmembrane receptor-like and cytosolic forms. Although the exact biological functions of these enzymes are largely unknown, they are believed to counter-balance the effects of protein tyrosine kinases. We have previously identified and characterized a mammalian transmembrane protein tyrosine phosphatase, called LAR (leukocyte common antigen related gene), whose expression is often associated with proliferating epithelial cells or epithelial progenitor cells. This study investigates the potential role of LAR in the regulation of cell growth and death in mammals.
We overexpressed in mammalian cells in culture either the full-length wild-type LAR or a truncation mutant containing only the extracellular domain of the molecule, and found that whereas the truncated LAR could be readily overexpressed in various cell lines, cells overexpressing the wild-type LAR were negatively selected. Using an inducible expression system, we demonstrated that overexpression of the wild-type LAR, but not the truncated LAR, activated the caspase pathway directly and induced p53-independent apoptosis.
Our data suggest that LAR might regulate cellular signals essential for cell survival. Overproduction of LAR may tilt the balance between the tyrosine phosphorylation and dephosphorylation of proteins whose activities are critical for cell survival, and therefore lead to cell death. In addition, our observations that overexpression of LAR induces cell death without affecting cell adhesion suggest that LAR may activate the caspase pathway and induce cell death directly. This work is the first example of the involvement of a receptor-like protein tyrosine phosphatase in cell-death control and provides the basis for searching for molecules and mechanisms linking signal transduction by protein tyrosine phosphorylation to the caspase-mediated cell-death pathway.
蛋白质酪氨酸磷酸酶家族包括跨膜受体样和胞质形式。尽管这些酶的确切生物学功能大多未知，但人们认为它们可抵消蛋白质酪氨酸激酶的作用。我们先前已鉴定并表征了一种哺乳动物跨膜蛋白酪氨酸磷酸酶，称为LAR（白细胞共同抗原相关基因），其表达常与增殖的上皮细胞或上皮祖细胞相关。本研究调查了LAR在哺乳动物细胞生长和死亡调控中的潜在作用。
我们在培养的哺乳动物细胞中过表达了全长野生型LAR或仅包含该分子胞外结构域的截短突变体，发现虽然截短的LAR能在各种细胞系中轻易过表达，但过表达野生型LAR的细胞被阴性选择。使用诱导表达系统，我们证明野生型LAR而非截短的LAR的过表达直接激活了半胱天冬酶途径并诱导了不依赖p53的细胞凋亡。
我们的数据表明LAR可能调节细胞存活所必需的细胞信号。LAR的过量产生可能会打破对细胞存活至关重要的蛋白质酪氨酸磷酸化和去磷酸化之间的平衡，从而导致细胞死亡。此外，我们观察到LAR的过表达诱导细胞死亡而不影响细胞黏附，这表明LAR可能激活半胱天冬酶途径并直接诱导细胞死亡。这项工作是受体样蛋白质酪氨酸磷酸酶参与细胞死亡控制的首个实例，并为寻找将蛋白质酪氨酸磷酸化的信号转导与半胱天冬酶介导的细胞死亡途径联系起来的分子和机制提供了基础。
