Boonyaratanakornkit V, Scott M P, Ribon V, Sherman L, Anderson S M, Maller J L, Miller W T, Edwards D P
University of Colorado School of Medicine, Pathology Department and Molecular Biology Program, Denver, CO 80262, USA.
Mol Cell. 2001 Aug;8(2):269-80. doi: 10.1016/s1097-2765(01)00304-5.
Steroid hormones have rapid nongenomic effects on cell-signaling pathways, but the receptor mechanisms responsible for this are not understood. We have identified a specific polyproline motif in the amino-terminal domain of conventional progesterone receptor (PR) that mediates direct progestin-dependent interaction of PR with SH3 domains of various cytoplasmic signaling molecules, including c-Src tyrosine kinases. Through this interaction, PR is a potent activator of Src kinases working by an SH3 domain displacement mechanism. By mutagenesis, we also show that rapid progestin-induced activation of Src and downstream MAP kinase in mammalian cells is dependent on PR-SH3 domain interaction, but not on the transcriptional activity of PR. Preliminary evidence for the biological significance of this PR signaling pathway through regulatory SH3 domains was shown with respect to an influence on progestin-induced growth arrest of breast epithelial cells and induction of Xenopus oocyte maturation.
类固醇激素对细胞信号通路具有快速的非基因组效应，但其背后的受体机制尚不清楚。我们在传统孕酮受体（PR）的氨基末端结构域中鉴定出一个特定的多脯氨酸基序，该基序介导PR与包括c-Src酪氨酸激酶在内的各种细胞质信号分子的SH3结构域之间直接的孕激素依赖性相互作用。通过这种相互作用，PR是通过SH3结构域置换机制发挥作用的Src激酶的有效激活剂。通过诱变，我们还表明，孕激素在哺乳动物细胞中快速诱导的Src和下游MAP激酶激活依赖于PR-SH3结构域相互作用，而不依赖于PR的转录活性。关于这种通过调节性SH3结构域的PR信号通路对孕激素诱导的乳腺上皮细胞生长停滞和非洲爪蟾卵母细胞成熟诱导的影响，显示了其生物学意义的初步证据。
