Saxena M, Williams S, Taskén K, Mustelin T
Laboratory of Signal Transduction, Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Nat Cell Biol. 1999 Sep;1(5):305-11. doi: 10.1038/13024.
The haematopoietic protein tyrosine phosphatase (HePTP) is a negative regulator of the MAP kinases Erk1, Erk2 and p38. HePTP binds to these kinases through a kinase-interaction motif (KIM) in its non-catalytic amino terminus and inactivates them by dephosphorylating the critical phosphorylated tyrosine residue in their activation loop. Here we show that cyclic-AMP-dependent protein kinase (PKA) phosphorylates serine residue 23 in the KIM of HePTP in vitro and in intact cells. This modification reduces binding of MAP kinases to the KIM, an effect that is prevented by mutation of serine 23 to alanine. The PKA-mediated release of MAP kinase from HePTP is sufficient to activate the kinase and to induce transcription from the c-fos promoter. Expression of a HePTP serine-23-to-alanine mutant inhibits MAP-kinase dissociation and activation and induction of transcription from the c-fos promoter. We conclude that HePTP not only controls the activity of MAP kinases, but also mediates crosstalk between the cAMP system and the MAP-kinase cascade.
造血蛋白酪氨酸磷酸酶（HePTP）是丝裂原活化蛋白激酶（MAP激酶）Erk1、Erk2和p38的负调控因子。HePTP通过其非催化性氨基末端的激酶相互作用基序（KIM）与这些激酶结合，并通过使其激活环中的关键磷酸化酪氨酸残基去磷酸化来使其失活。我们在此表明，环磷酸腺苷依赖性蛋白激酶（PKA）在体外和完整细胞中使HePTP的KIM中的丝氨酸残基23磷酸化。这种修饰减少了MAP激酶与KIM的结合，将丝氨酸23突变为丙氨酸可防止这种效应。PKA介导的MAP激酶从HePTP的释放足以激活该激酶并诱导c-fos启动子的转录。HePTP丝氨酸23突变为丙氨酸的突变体的表达抑制了MAP激酶的解离和激活以及c-fos启动子转录的诱导。我们得出结论，HePTP不仅控制MAP激酶的活性，还介导cAMP系统与MAP激酶级联之间的串扰。
