Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase
Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase
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DOI：
10.1074/jbc.m203901200
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发表时间：
2003-02-28
影响因子：
4.8
通讯作者：
Hunzicker-Dunn, M
中科院分区：
文献类型：
--
作者：
Cottom, J;Salvador, LM;Hunzicker-Dunn, M
在这篇报道中，我们试图阐明卵泡刺激素(FSH)受体信号促进颗粒细胞p42/p44细胞外信号调节蛋白激酶(ERKs)激活的机制。结果表明，在赋形剂处理的细胞中，ERK激酶MEK和上游中间产物Raf-1、Ras、Src和L型钙通道已经部分激活，而FSH不再进一步激活它们。这种紧张性刺激途径似乎在ERK的水平上受到一个100 kDa的磷酸酪氨酸磷酸酶的抑制，该酶与载体处理的细胞中的ERK结合，并促进其调节的Tyr残基的去磷酸化，导致ERK失活。FSH促进磷酸化酪氨酸磷酸酶的磷酸化及其与ERK的解离，解除ERK的抑制，导致其通过紧张性刺激途径被激活，继而移位到细胞核。与这一前提一致，FSH刺激的ERK激活可被细胞通透性蛋白激酶A特异性抑制肽Myr-PKI、MEK抑制剂、钙通道阻滞剂Src和细胞外钙离子的螯合作用所抑制。这些结果表明，FSH通过解除100 kDa磷酸酪氨酸磷酸酶的抑制，刺激未成熟颗粒细胞中ERK的活性。
In this report we sought to elucidate the mechanism by which the follicle-stimulating hormone (FSH) receptor signals to promote activation of the p42/p44 extracellular signal-regulated protein kinases (ERKs) in granulosa cells. Results show that the ERK kinase MEK and upstream intermediates Raf-1, Ras, Src, and L-type Ca2+ channels are already partially activated in vehicle-treated cells and that FSH does not further activate them. This tonic stimulatory pathway appears to be restrained at the level of ERK by a 100-kDa phosphotyrosine phosphatase that associates with ERK in vehicle-treated cells and promotes dephosphorylation of its regulatory Tyr residue, resulting in ERK inactivation. FSH promotes the phosphorylation of this phosphotyrosine phosphatase and its dissociation from ERK, relieving ERK from inhibition and resulting in its activation by the tonic stimulatory pathway and consequent translocation to the nucleus. Consistent with this premise, FSH-stimulated ERK activation is inhibited by the cell-permeable protein kinase A-specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK, Src, a Ca2+ channel blocker, and chelation of extracellular Ca2+. These results suggest that FSH stimulates ERK activity in immature granulosa cells by relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase.