Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling.
Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling.
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DOI：
10.1016/j.biocel.2010.04.016
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发表时间：
2010-09
影响因子：
4
通讯作者：
Hamel, Paul A.
中科院分区：
文献类型：
--
作者：
Chang, Hong;Li, Qing;Moraes, Ricardo C.;Lewis, Michael T.;Hamel, Paul A.
Hedgehog（Hh）信号传导通过Patched-1（Ptch 1）受体介导。Hh-结合Ptch 1阻断Ptch 1对跨膜蛋白Smoothened（Smo）活性的抑制作用，导致Gli-家族转录因子诱导靶基因。我们在这里证明，HH结合Ptch 1刺激Erk 1/2的激活。这种激活对小分子Smo拮抗剂不敏感，并且发生在不表达Smo的细胞系中。具体而言，Ptch 1的C-末端含有编码I类和II类SH 3结合位点的基序。使用GST-c-srcSH 3、-Grb 2SH 3和-p85β SH 3融合蛋白验证SH 3结构域结合活性。异位表达的Grb 2或p85β也可以与Ptch 1 C末端共免疫沉淀。此外，血清饥饿的人乳腺上皮细胞和Shh光II成纤维细胞刺激Erk 1/2的磷酸化。Erk 1/2激活观察到Smo活性已被抑制使用环巴胺和乳腺上皮细胞系，MCF 10A，不表达Smo的细胞。这些数据揭示了Ptch 1的C-末端区域的新的结合活性，并定义了由独立于需要Smo的途径操作的Hh-配体刺激的信号传导途径。
Hedgehog (Hh) signalling is mediated through the Patched-1 (Ptch1) receptor. Hh-binding to Ptch1 blocks the inhibitory effects of Ptch1 on the activity of the transmembrane protein, Smoothened (Smo), resulting induction of target genes by the Gli-family of transcription factors. We demonstrate here that Hh-binding to Ptch1 stimulates activation of Erk1/2. This activation is insensitive to the small molecule Smo antagonists and occurs in a cell line that does not express Smo. Specifically, the C-terminus of Ptch1 harbors motifs encoding Class I and II SH3-binding sites. SH3-domain binding activity was verified using GST-c-srcSH3, -Grb2SH3 and -p85βSH3 fusion-proteins. Ectopically-expressed Grb2 or p85β could also be co-immunoprecipitated with the Ptch1 C-terminus. Addition of Shh to serum-starved human mammary epithelial cells and Shh Light II fibroblasts stimulated phosphorylation of Erk1/2. Erk1/2 activation was observed in cells where Smo activity had been inhibited using cyclopamine and in the breast epithelial cell line, MCF10A, that does not express Smo. These data reveal novel binding activities for the C-terminal region of Ptch1 and define a signalling pathway stimulated by the Hh-ligands operating independently of pathways requiring Smo.
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影响因子：
11.4
作者：
Barnes, EA;Kong, M;Donoghue, DJ
通讯作者：
Donoghue, DJ
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
DOI：
10.1083/jcb.200401077
发表时间：
2004-08-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fu M;Lui VC;Sham MH;Pachnis V;Tam PK
通讯作者：
Tam PK
影响因子：
10.5
作者：
Alexandre, C;Jacinto, A;Ingham, PW
通讯作者：
Ingham, PW
影响因子：
2.1
作者：
Kasai, K;Takahashi, M;Arnheiter, H
通讯作者：
Arnheiter, H